Peptides Having Anti-Inflammatory Properties

ABSTRACT

Aspects of the present invention relate to peptides having anti-inflammatory activity, compositions containing one or more of the peptides, and use of the peptides to treat conditions associated with excessive inflammation in animals, particularly humans and other mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. §119 (e), this application claims the benefit ofpriority to U.S. Provisional Patent Application Ser. No. 62/063,909,filed Oct. 14, 2014, the disclosure of which application is herebyincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

Aspects of the present invention relate to peptides havinganti-inflammatory activity, compositions containing one or more of thepeptides, and use of the peptides to treat conditions associated withexcessive inflammation in animals, particularly humans and othermammals.

BACKGROUND OF THE INVENTION

Under normal conditions, inflammation is a process that helps an animalrecover from injury. Acute inflammation is the initial response of atissue to harmful stimuli. It involves a complex, highly regulatedprocess that begins when cells present in the injured tissue, includingmacrophages, dendritic cells, histiocytes, Kupffer cells, andmastocytes, sense molecules associated with the injury and becomeactivated. Upon activation, these cells release inflammatory mediators,such as vasodilators. The vasodilators induce increased blood flow andpermeability of the blood vessels in the vicinity of the injury. This,in turn, results in the increased movement of plasma and leukocytes(including neutrophils and macrophages) from the blood into the injuredtissue. Because inflammatory mediators are, in general, rapidlydegraded, acute inflammation requires constant stimulation in order tobe sustained. As a result, acute inflammation ends once the harmfulstimulus is removed.

Various agents, including but not limited to bacteria, viruses, physicalinjury, chemical injury, cancer, chemotherapy, and radiation therapy,can, depending on the specific agent and the genetic makeup of theanimal exposed to it, cause prolonged and excessive inflammation. Suchinflammation, known as chronic inflammation, is believed to be acontributing factor to many widespread and debilitating diseases,including heart disease, cancer, respiratory disease, stroke,neurological diseases such as Alzheimer's disease, diabetes, and kidneydisease. The result of chronic inflammation is the destruction of normaltissue and its replacement with collagen-rich connective tissue.Collagen-rich connective tissue, also known as scar tissue, exhibitsdiminished tissue function as compared to normal tissue. Persistent andprolonged formation of scar tissue, in turn, leads to fibrosis. Fibrosisis among the common symptoms of diseases affecting the lungs, skin,liver, heart, and bone marrow, and is a critical factor in diseases suchas idiopathic pulmonary fibrosis, scleroderma, keloids, liver cirrhosis,myocardial fibrosis, diabetic kidney disease, myelodysplastic syndrome,and other disorders.

Studies of chronic inflammation and fibrosis have indicated that,regardless of the activating agent and the tissue affected, a commonnetwork of signaling proteins tend to function together to establish thepro-inflammatory state. This network of signaling proteins includes anumber of different cytokines, cytokine receptors, transcriptionfactors, and micro RNAs, including TGFβ, TGFβRII, and miRNA19b.

Despite growing knowledge about conditions that involve excessiveinflammation, such as chronic inflammation and fibrosis, treatments forsuch conditions remain elusive. Many drugs and other substances havebeen shown to have anti-inflammatory activity, either in vitro or invivo, but for many indications caused or potentiated by inflammation,there are still no therapies. In addition, many anti-inflammatorytherapies are associated with harmful side effects. Thus, there remainsa critical need to identify therapeutic agents that reduce inflammationwithout harmful side effects.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the discovery of novelpeptides that have powerful anti-inflammatory activities in vitro and invivo. The present invention is also based, in part, on the discoverythat peptides of the invention specifically bind to key functionalregions on one or more signaling proteins, particularly pro-inflammatorycytokines, macrophage inhibition proteins, and histone regulationproteins. The present invention is also based, in part, on the discoverythat the peptides of the invention are sufficiently stable in thecirculation to allow for intravenous administration.

Accordingly, in one aspect, the invention provides a compositioncomprising an anti-inflammatory polypeptide. In certain embodiments, theanti-inflammatory polypeptide is 3 to 24 amino acids residues in lengthand includes a striapathic region consisting of alternating hydrophobicand hydrophilic modules. In certain embodiments, each hydrophilic moduleis made up of a sequence of one or more (e.g., 1-5, 1-4, 1-3)hydrophilic amino acid residues. In certain embodiments, eachhydrophobic module is made up of a sequence of one or more (e.g., 1-5,1-4, 1-3) hydrophobic amino acid residues.

In certain embodiments, the striapathic region of an anti-inflammatorypeptide includes m hydrophilic modules and n hydrophobic modules, with mand n each being a positive integer. For example, in certainembodiments, the striapathic region includes two hydrophilic modules andtwo hydrophobic modules (2:2), two hydrophilic modules and threehydrophobic modules (2:3), three hydrophilic modules and two hydrophobicmodules (3:2), three hydrophilic modules and three hydrophobic modules(3:3), three hydrophilic modules and four hydrophobic modules (3:4), orfour hydrophilic modules and three hydrophobic modules (4:3).

In certain embodiments, the striapathic region of an anti-inflammatorypolypeptide is at least 5, 6, 7, 8, 9, or 10 amino acid residues inlength. In preferred embodiments, the length of the striapathic regionis between 7 and 12 amino acid residues. In certain embodiments, thestriapathic region makes up at least 25% of the length of thepolypeptide. For example, in certain embodiments, the striapathic regioncomprises at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or 100% of the length of the polypeptide.

In certain embodiments, the striapathic region of an anti-inflammatorypolypeptide adopts a helical secondary structure. Examples of helicalsecondary structures include 3₁₀-helices, α-helices, π-helices, andpoly-proline helices. In other embodiments, the striapathic region of ananti-inflammatory polypeptide adopts a beta-strand secondary structure.In preferred embodiments, the striapathic region of an anti-inflammatorypolypeptides has an amphipathic conformation.

In certain embodiments, an anti-inflammatory polypeptide comprises,consists essentially of, or consists of a striapathic region having asequence that conforms to any one of the structural formulas disclosedherein (e.g., any one of Formulas I-LIII). In certain embodiments, theanti-inflammatory polypeptide is one of the polypeptides listed inTables 3-9. In other embodiments, the anti-inflammatory polypeptide hasat least 70%, 80%, or 90% homology with any one of the polypeptidesdisclosed in Tables 3-9.

In certain embodiments, an anti-inflammatory polypeptide binds to atleast one signaling protein. In preferred embodiments, theanti-inflammatory polypeptide binds to at least one signaling protein invitro and/or in vivo, with sufficient affinity to modulate the activityof the signaling protein. Examples of signaling proteins that theanti-inflammatory polypeptides bind to include proteins that function aspro-inflammatory cytokines, proteins that inhibit macrophage activity,or protein that regulate histone function. In certain embodiments, theanti-inflammatory polypeptide binds to a protein target selected fromthe group consisting of NFkB class II proteins (e.g., Rel A, Rel B,cRel, NF-kB1, and NF-kB2). TGFβ, Notch receptors (e.g., Notch1), Wntreceptors (e.g., Wnt8R). TRAIL, EGFR, interleukin receptors (e.g., IL6R,IL10R), cyclin dependent kinases (e.g., CDK6), CD47, SIRP-α,transglutaminases (e.g., TGM2), LEGUMAIN, CD209, FAS, programmed celldeath protein 1 (PD-1/CD279), mitogen-activated protein kinase kinase 7(MKK7), ribonucleotide reductase (RNR), and histone methyl transferase.In preferred embodiments, the anti-inflammatory polypeptide binds totwo, three, four, or more such signaling proteins. For example, incertain embodiments, an anti-inflammatory polypeptide binds to an NF-kBClass II protein (e.g., RelB) and at least one other signaling proteinthat functions as a pro-inflammatory cytokine, an inhibitor ofmacrophage activity, or a regulator of histone function. In preferredembodiments, the anti-inflammatory polypeptide binds to the NF-kB ClassII protein and at least one other protein target, with sufficientbinding affinity to each target to modulate the activity of both targetsin vivo. In preferred embodiments, an anti-inflammatory polypeptidebinds to the dimerization site of an NFkB Class II protein (e.g., RelB).

In certain embodiments, an anti-inflammatory polyeptides binds to acarrier protein in the blood (e.g., serum albumin).

In certain embodiments, an anti-inflammatory polypeptide is modified toinclude, for example, a linker, a carbohydrate, a lipid, or a polymer(e.g., PEG). In certain embodiments, a first anti-inflammatorypolyeptide is linked to a second anti-inflammatory polypeptide so as toform a multimer, such as a dimer. In certain embodiments, the dimer is ahomodimer. In other embodiments, the dimer is a heterodimer. In certainembodiments, the linker is a peptide linker. In preferred embodiments,the peptide linker forms a peptide bond with the C-terminus of the firstanti-inflammatory polypeptide and a peptide bond with the N-terminus ofthe second anti-inflammatory polypeptide. In certain embodiments, thelinker is a biodegradeable linker. In certain embodiments, the linker isa disulfide bond. In certain embodiments, the disulfide linkage isformed by a pair of cysteine residues (e.g., one cysteine residue fromeach of the polypeptides being linked).

In certain embodiments, the anti-inflammatory polypeptide is linked to amolecule other than another anti-inflammatory polypeptide. For example,the anti-inflammatory polypeptide can be linked to a label or achemotherapeutic agent. In certain embodiments, the linker is abiodegradable linker. In certain embodiments, the linker is a di-sulfidebond (e.g., involving the sulfhydryl group of a cysteine residue locatedat the C-terminus or N-terminus of the anti-inflammatory polypeptide).

In another aspect, the invention provides pharmaceutical compositionsthat comprise an anti-inflammatory polypeptide and a pharmaceuticallyacceptable carrier. In certain embodiments, the pharmaceuticalcomposition comprises a single type of anti-inflammatory polypeptide. Inother embodiments, the pharmaceutical composition comprises acombination of two or more anti-inflammatory polypeptides. In preferredembodiments, the pharmaceutical composition is substantially free ofblood proteins and/or metabolites found in the blood. In otherembodiments, the pharmaceutical composition includes serum albumin(e.g., human serum albumin). In preferred embodiments, any serum albuminpresent in a pharmaceutical composition is recombinantly produced and/orsubstantially free of other blood proteins and/or metabolites found inthe blood. In certain embodiments, the pharmaceutical compositioncomprises 1 mg to 1000 mg (e.g., 10 to 400 mg, 20 to 300 mg, or about 25to 250 mg) of an anti-inflammatory polypeptide.

In another aspect, the invention provides methods of treating a subjectby administering to the subject a composition (e.g., a pharmaceuticalcomposition) comprising an anti-inflammatory polypeptide. In certainembodiments, the subject is an animal, such as a mammal (e.g., a human).In certain embodiments, the subject has elevated levels of inflammatorycytokines, is suffering from a chronic inflammatory condition, or islikely to develop a chronic inflammatory condition. In certainembodiments, the chronic inflammatory condition can be irritable boweldisease, ulcerative colitis, colitis, Crohn's disease, fibrosis,idiopathic pulmonary fibrosis, asthma, keratitis, arthritis,osteoarthritis, rheumatoid arthritis, an auto-immune disease, a felineor human immunodeficiency virus (FIV or HIV) infection, or cancer. Incertain embodiments, the cancer is colon cancer, breast cancer,leukemia, lymphoma, ovarian cancer, prostate cancer, liver cancer, lungcancer, testicular cancer, cervical cancer, bladder cancer, endometrialcancer, kidney cancer, melanoma, or a cancer of the thyroid or brain. Incertain embodiments, the composition is administered in combination witha chemotherapeutic agent, immunotherapeutic agent, and/or radiationtherapy.

These and other features and advantages of the compositions and methodsof the invention will be set forth or will become more fully apparent inthe description that follows and in the appended claims. For example,suitable anti-inflammatory polypeptides may be identified by use of theStructural Algorithm described herein. Furthermore, features andadvantages of the described compositions and methods may be learned bypracticing the methods or will be obvious from the description.

BRIEF SUMMARY OF THE DRAWINGS

FIG. 1 depicts a structural model of human RelB, an NF-kB Class IIprotein.

FIG. 2 depicts a structural model of human RelB bound by RP-182.

FIG. 3 depicts a structural model of human RelB bound by RP-166.

FIG. 4 depicts a structural model of human RelB bound by RP-113.

FIG. 5 depicts a structural model of human RelB bound by RP-387.

FIG. 6 depicts a structural model of human RelB bound by RP-289.

FIG. 7 depicts a structural model of human RelB bound by NF-Contr2.

FIG. 8 depicts a structural model of human RelB bound by NF-Contr3.

FIG. 9 depicts structural models of polypeptides RP-182. RP-166, RP-113,and RP-289, with each model showing the polar and non-polar facial arcassociated with the helices formed by the polypeptides.

FIG. 10 depicts structural models of polypeptides RP-387, NF-Contr2, andNF-Contr3, with each model showing the polar and non-polar amino acidresidues. The facial arc associated with the helix formed by RP-387 isalso shown.

FIG. 11 depicts a structural model of the binding pocket of the RelBdimerization domain.

FIG. 12 depicts a structural model of the binding pocket of the RelBdimerization domain bound by RP-183.

FIG. 13 depicts a structural model of histone methyl transferase enzymebound by RP-182.

FIG. 14 depicts structural models of a CD47 dimer (left panel) and aCD47 dimer bound by RP-183.

FIG. 15 depicts structural models of a SIRP-α dimer (left panel) and aSIRP-α dimer bound by RP-183.

FIG. 16 depicts structural models of CD206 (left side) and CD206 boundby RP-182 (right side).

FIG. 17 depicts structural models of TGM2 (left side) and TGM2 bound byRP-182 (right side).

FIG. 18 depicts a structural model of human serum albumin bound byRP-183.

FIG. 19 shows PD-1-stained tumor cells from p53/KRAS mice treated withvehicle only (left panel) or treated with RP-182 (right panel). PD-1expression is reduced in RP-182 treated mice.

FIG. 20 shows PD-L1-stained (left panels) and PD-L2-stained (rightpanels) tumor cells from p53/KRAS mice treated with vehicle only (toppanel in each set) or treated with RP-182 (bottom panel in each set).PD-L1 and PD-L2 expression is reduced in RP-182 treated mice.

FIG. 21 shows MDA-MB-231 tumor volume in four cohorts of mice over time.Cohort 1: vehicle; Cohort 2: Gemcitabine treated; Cohort 3: RP-182treated; Cohort 4: RP-182+Gemcitabine treated.

FIG. 22 shows C42B tumor volume in four cohorts of mice over time.Cohort 1: vehicle; Cohort 2: Docetaxel treated; Cohort 3: RP-182treated; Cohort 4: RP-182+Docetaxel treated.

DETAILED DESCRIPTION OF THE INVENTION

The following description supplies specific details in order to providea thorough understanding of the present invention. That said, to avoidobscuring aspects of the described anti-inflammatory polypeptides andrelated methods of treating a subject, well-known structures, materials,processes, techniques, and operations are not shown or described indetail. Additionally, the skilled artisan will understand that thedescribed anti-inflammatory polypeptides and related methods of treatinga subject can be implemented and used without employing these specificdetails. Indeed, the described anti-inflammatory polypeptides andmethods can be placed into practice by modifying the illustratedpolypeptides, compositions, and methods, and can be used in conjunctionwith other treatments, apparatuses, and techniques conventionally usedin the industry.

As discussed above, the invention disclosed herein relates toimmune-modulatory polypeptides, particularly peptides that haveimmunosuppressive properties, and methods of administering suchimmune-modulatory polypeptides to a subject, particularly a subjectsuffering from a medical condition associated with persistentinflammation or at risk developing such a medical condition.

The invention provides anti-inflammatory polypeptides, sometimesreferred to as “RP peptides.” that satisfy the requirements of theStructural Algorithm described below. The invention also providesanti-inflammatory polypeptides that share a minimum degree of homologywith any of the exemplary RP peptides disclosed herein. Thus, a peptideor polypeptide of the invention is an anti-inflammatory polypeptide thatsatisfies the Structural Algorithm described below or shares a minimumdegree of homology with any of the exemplary RP peptides disclosedherein (e.g., in Tables 3-9).

The terms “peptide” and “polypeptide” are used synonymously herein torefer to polymers constructed from amino acid residues.

The term “amino acid residue,” as used herein, refers to any naturallyoccurring amino acid (L or D form), non-naturally occurring amino acid,or amino acid mimetic (such as a peptoid monomer).

The “length” of a polypeptide is the number of amino acid residueslinked end-to-end that constitute the polypeptide, excluding anynon-peptide linkers and/or modifications that the polypeptide maycontain.

The term “striapathic region,” as used herein, refers to an alternatingsequence of hydrophobic and hydrophilic modules. A “hydrophobic module”is made up of a peptide sequence consisting of one to five hydrophobicamino acid residues. Likewise, a hydrophilic module is made up of apeptide sequence consisting of one to five hydrophilic amino acidresidues.

Hydrophobic amino acid residues are characterized by a functional group(“side chain”) that has predominantly non-polar chemical properties.Such hydrophobic amino acid residues can be naturally occurring (L or Dform) or non-naturally occurring. Alternatively, hydrophobic amino acidresidues can be amino acid mimetics characterized by a functional group(“side chain”) that has predominantly non-polar chemical properties.Conversely, hydrophilic amino acid residues are characterized by afunctional group (“side chain”) that has predominantly polar (charged oruncharged) chemical properties. Such hydrophilic amino acid residues canbe naturally occurring (L or D form) or non-naturally occurring.Alternatively, hydrophilic amino acid residues can be amino acidmimetics characterized by a functional group (“side chain”) that haspredominantly polar (charged or uncharged) chemical properties. Examplesof hydrophilic and hydrophobic amino acid residues are shown in Table 1,below. Suitable non-naturally occurring amino acid residues and aminoacid mimetics are known in the art. See, e.g., Liang et al. (2013), “AnIndex for Characterization of Natural and Non-Natural Amino Acids forPeptidomimetics.” PLoS ONE 8(7):e67844.

Although most amino acid residues can be considered as eitherhydrophobic or hydrophilic, a few, depending on their context, canbehave as either hydrophobic or hydrophilic. For example, due to theirrelatively weak non-polar characteristics, glycine, proline, and/orcysteine can sometimes function as hydrophilic amino acid residues.Conversely, due to their bulky, slightly hydrophobic side chains,histidine and arginine can sometimes function as hydrophobic amino acidresidues.

TABLE 1 Hydrophobic and Hydrophilic Amino Acid Residues HydrophilicResidues Hydrophobic Residues (X) (Y) Arginine Tryptophan HistidinePhenylalanine Lysine Tyrosine Aspartic Acid Isoleucine Glutamic AcidLeucine Asparagine Valine Glutamine Methionine Pyrrolysine CysteineThreonine Serine Alanine Proline Glycine SelenocysteineN-formylmethionine Norleucine Norvaline

The term “anti-inflammatory property,” as used herein, refers to anyproperty of a polypeptide that can be evaluated in silico, in vitro,and/or in vivo, that reduces or inhibits, or would be expected to reduceor inhibit, a pro-inflammatory signal mediated by a protein targetand/or reduces or inhibits inflammation in a subject.

Structural Algorithm

In its most basic form, the Structural Algorithm requires ananti-inflammatory peptide to have the following characteristics:

a length of 3 to 24 amino acid residues;

a striapathic region that comprises at least 25% of the length of thepolypeptide; and

at least one anti-inflammatory property.

The anti-inflammatory peptide and/or its striapathic region can have alength that is greater than 3 amino acid residues and/or less than 24amino acid residues. Thus, the requisite length of the polypeptide canbe, for example, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 4 to 20, 4to 18, 4 to 16, 4 to 14, 4 to 12, 5 to 20, 5 to 18, 5 to 16, 5 to 14, 5to 12, 6 to 20, 6 to 18, 6 to 16, 6 to 14, 6 to 12, 7 to 20, 7 to 18, 7to 16, 7 to 14, or in certain embodiments 7 to 12 amino acid residues.For an anti-inflammatory polypeptide that is longer than 12 amino acidresidues, it can be advantageous to design a kink in the secondarystructure (e.g., such as produced by a proline residue) such that thepolypeptide has a striapathic region that is 12 or fewer amino acidresidues in length. The striapathic region of an anti-inflammatorypeptide can comprise at least 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, or 100% of the length of the polypeptide.

An anti-inflammatory polypeptide can have a striapathic region thatincludes at least two hydrophobic modules and one or more (e.g., two orthree) hydrophilic modules. Alternatively, an anti-inflammatorypolypeptide can have a striapathic region that includes at least threehydrophobic modules and two or more (e.g., three or four) hydrophilicmodules; a striapathic region that includes at least two hydrophilicmodules and one or more (e.g., two or three) hydrophilic modules; or astriapathic region that includes at least three hydrophilic modules andtwo or more (e.g., three or four) hydrophobic modules.

As discussed above, a striapathic region consists of alternatinghydrophilic (X_(m)) and hydrophobic (Y_(n)) modules. In this context,the subscripts m and n are positive integers that identify differentmodules. Each X_(m) module consists of a sequence according to theformula X_(ma)-X_(mb)-X_(mc)-X_(md)-X_(me). X_(ma) is selected from thegroup consisting of a naturally occurring hydrophilic amino acid, anon-naturally occurring hydrophilic amino acid, and a hydrophilic aminoacid mimetic; and X_(mb), X_(mc), X_(md), and X_(me) are eachindividually absent or selected from the group consisting of a naturallyoccurring hydrophilic amino acid, a non-naturally occurring hydrophilicamino acid, and a hydrophilic amino acid mimetic. Each Y_(n) moduleconsists of a sequence according to the formulaY_(na)-Y_(nb)-Y_(nc)-Y_(nd)-Y_(ne). Y_(na) is selected from the groupconsisting of a naturally occurring hydrophobic amino acid, anon-naturally occurring hydrophobic amino acid, and a hydrophobic aminoacid mimetic; Y_(nb), Y_(nc), Y_(nd), and Y_(ne) are each individuallyabsent or selected from the group consisting of a naturally occurringhydrophobic, a non-naturally occurring hydrophobic amino acid, and ahydrophobic amino acid mimetic.

In certain anti-inflammatory polypeptides, each X_(m) module consists ofa sequence according to the formula X_(ma)-X_(mb)-X_(mc)-X_(md) orX_(ma)-X_(mb)-X_(mc). Similarly, in certain anti-inflammatorypolypeptides, each Y_(n) module consists of a sequence according to theformula Y_(na)-Y_(nb)-Y_(nc)-Y_(nd) or Y_(na)-Y_(nb)-Y_(nc).

Anti-inflammatory peptides can include a striapathic regioncorresponding to a formula selected from the group consisting of:

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (Formula I);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)  (FormulaII);

X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaIII);

X_(1a)-X_(1b)-X_(1c)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)  (Formula IV);

Y_(1a)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-X_(3a)  (FormulaV);

X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)  (Formula VI);

Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (Formula VII);

Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaVIII);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)  (FormulaIX);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-X_(3a)  (FormulaX);

X_(1a)-Y_(1a)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)  (FormulaXI);

X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)  (FormulaXII);

Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)  (FormulaXIII);

X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaXIV);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)  (FormulaXV);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (FormulaXVI);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)  (Formula XVII);

X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)  (FormulaXVIII);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaXIX);

X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)  (FormulaXX);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)  (FormulaXXI);

X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-X_(3a)-Y_(3a)-Y_(3b)  (FormulaXXII);

Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaXXIII);

X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)  (Formula XXIV);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)-X_(3b)  (FormulaXXV);

X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)-Y_(3c)  (FormulaXXVI);

X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)  (Formula XXVII);

X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)  (FormulaXXVIII);

Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)-X_(2a)  (FormulaXXIX);

X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)  (FormulaXXX);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-X_(2b)  (FormulaXXXI);

X_(1a)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)-X_(3c)-Y_(3a)-Y_(3b)-Y_(3c)  (FormulaXXXII);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)  (Formula XXXIII);

Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(1a)-X_(1b)-X_(1c)-X_(1d)  (FormulaXXXIV);

X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(2a)-X_(2b)-X_(2c)-X_(2d)-Y_(2a)  (FormulaXXXV);

Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)  (FormulaXXXVI);

X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-Y_(2b)  (FormulaXXXVII);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1a)-X_(1c)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)  (FormulaXXXVIII);

Y_(1a)-X_(1b)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)  (Formula XXXIX);

Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)  (FormulaXL);

Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaXLI);

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)  (FormulaXLII);

Y_(1a)-Y_(1b)-Y_(1c)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)  (FormulaXLIII);

X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)  (Formula XLIV);

X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)-X_(2d)  (FormulaXLV);

X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)  (FormulaXLVI);

X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)  (FormulaXLVII);

X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)  (FormulaXLVIII);

Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)  (Formula XLIX);

Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)-Y_(4a)  (FormulaL);

X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-X_(2a)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)  (FormulaLI);

Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(1a)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)  (FormulaLII);

Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2b)-Y_(3a)-X_(3a)-Y_(4a)  (FormulaLIII); and

Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-Y_(3b)-Y_(3c)-X_(3a)-Y_(4a)-Y_(4b)  (FormulaLIV).

Typically, the striapathic region (or a portion thereof) of ananti-inflammatory polypeptide will have an amphipathic conformation(e.g., under physiological conditions). To be considered amphipathic,the striapathic region (or portion thereof) need not be in theamphipathic conformation at all times. Rather, it is sufficient that theamphipathic conformation be present at least 50%, 60%, 70%, 80%, or moreof the time, or when the anti-inflammatory polypeptide is binding to atarget molecule, such as an NF-kB Class II protein (e.g., Rel B). Often,the amphipathic conformation will be associated with a particularsecondary structure, such as a helical structure. Thus, the striapathicregion (or a portion thereof) of the anti-inflammatory polypeptide canhave an amphipathic 3₁₀-helical conformation, an amphipathic α-helicalconformation, an amphipathic π-helical conformation, or an amphipathicpoly-proline helical conformation. Alternatively, the striapathic region(or a portion thereof) of the anti-inflammatory polypeptide can have anamphipathic β-strand conformation.

For anti-inflammatory peptides that comprise a striapathic region thatincludes or has an amphipathic helical conformation (e.g., 3₁₀-helical,α-helical, π-helical, or polyproline helical conformation), thehydrophobic surface (“side”) can have a facial arc of at least 100°. Incertain embodiments, the facial arc of the hydrophobic surface or sideis at least 125°, 150°, 175°, 200°, 225°, 250°, 275°, or 300°.

Anti-inflammatory polypeptides in certain embodiments have a striapathicregion that has a relatively large hydrophobic volume. Accordingly, thestriapathic region can optimally contain hydrophobic amino acid residueshaving a total side-chain volume of at least 600 cubic angstroms. Incertain embodiments, the hydrophobic amino acid residues of thestriapathic region have a hydrophobic side-chain volume of at least 650,700, 750, 800, 850, 900, 950, 1000, or more cubic angstroms.Alternatively, or in addition, the striapathic region can becharacterized by a ratio of the sum of the side-chain volume ofhydrophobic amino acid residues to the sum of the side-chain volume ofhydrophilic amino acid residues, wherein the ratio is at least 0.75 orhigher. For example, the ratio can be at least 0.8, 0.85, 0.9, 0.95,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3,2.4, 2.5, or greater.

Because of the desirability of a striapathic region having a relativelylarge hydrophobic side-chain volume, it is generally preferable toinclude one or more (e.g., 2, 3, 4, 5, or more) large hydrophobic aminoacid residues in the sequence of the striapathic region. Conversely, itis generally preferable to have two or fewer (e.g., 1 or 0) smallhydrophobic amino acid residues in the sequence of the striapathicregion. Examples of large hydrophobic amino acid residues includetryptophan, phenylalanine, and tyrosine. In addition, under certaincircumstances, histidine or arginine can be considered a largehydrophobic amino acid residue. Examples of small hydrophobic residuesinclude glycine, alanine, serine, cysteine, valine, threonine, andproline. Accordingly, an anti-inflammatory polypeptide can have astriapathic region that includes one or more (e.g., 2, 3, 4, 5, or more)hydrophobic residues selected from the group consisting of tryptophan,phenylalanine, and tyrosine. Alternatively, the anti-inflammatorypolypeptide can have a striapathic region that includes one or more(e.g., 2, 3, 4, 5, or more) hydrophobic residues selected from (i) thegroup consisting of tryptophan, phenylalanine, tyrosine, and histidine,or (ii) the group consisting of tryptophan, phenylalanine, tyrosine, andarginine. In certain embodiments, the anti-inflammatory polypeptide hasa striapathic region that includes two or fewer (e.g., 1 or 0)hydrophobic residues selected from the group consisting of glycine,alanine, serine, cysteine, valine, threonine, and proline.Alternatively, the anti-inflammatory polypeptide can have a striapathicregion that includes no more than one hydrophobic residue selected fromthe group consisting of glycine, alanine, serine, cysteine, valine,threonine, and proline. In other alternatives, the anti-inflammatorypolypeptide can have a striapathic region that includes no glycineresidues, no alanine residues, no scrine residues, no cysteine residues,no valine residues, no threonine residues, and/or no proline residues.

It is also preferable that an anti-inflammatory polypeptide have astriapathic region characterized by a moderate level of cationicity(i.e., a striapathic region that does not contain an excessive number ofamino acid residues having positively charged side chains). Examples ofamino acid residues having positively charged side groups (assumingphysiological conditions) includes lysine, typically arginine, andsometimes histidine. Examples of amino acid residues having negativelycharged side chains (assuming physiological conditions) include asparticacid and glutamic acid. Examples of hydrophilic amino acid residueshaving uncharged side chains (assuming physiological conditions) includeaspargine and glutamine. Accordingly, an anti-inflammatory polypeptidecan have a striapathic region that includes five or fewer (e.g., 4, 3,2) lysine residues. Alternatively, an anti-inflammatory polypeptide canhave a striapathic region that includes five or fewer (e.g., 4, 3, 2)amino acid residues selected from the group consisting of lysine andarginine. In other alternatives, an anti-inflammatory polypeptide canhave a striapathic region that includes five or fewer (e.g., 4, 3, 2)amino acid residues selected from the group consisting of lysine,arginine, and histidine. For anti-inflammatory polypeptides that have astriapathic region that includes one or more (e.g., two or more)positively charged amino acid residues, it can be advantageous for thestriapathic region to also include some negatively charged or polar,uncharged amino acid residues. For example, the anti-inflammatorypolypeptide can have a striapathic region that includes both positivelyand negatively charged amino acid residues, such that the net charge onthe polypeptide is no more than +2 or +1 (e.g., the number of positivelycharged amino acid residues does not exceed the number of negativelycharged amino acid residues by more than one or two). Alternatively, theanti-inflammatory polypeptide can have a striapathic region thatincludes both positively charged and polar, uncharged amino acidresidues, such that the net charge on the polypeptide is no more than +2or +1 (e.g., the number of positively charged amino acid residues doesnot exceed one or two). In other alternatives, the anti-inflammatorypolypeptide can have a striapathic region that includes both positivelycharged, negatively charged, and hydrophilic uncharged charged aminoacid residues, such that the net charge on the polypeptide is no morethan +2.

To avoid certain undesired interactions between RP peptides and othermolecules (whether another RP peptide, a metal ion, etc.) it can beadvantageous to limit the number of certain types of amino acid residuesin the polypeptide. For example, because cysteine residues formdi-sulfide bonds under certain conditions (e.g., oxidativeenvironments), it can be useful to limit the number of cysteine residuesin a polypeptide of the invention to no more than one or two, or evennone. Because histidine residues chelate metals under certain conditions(e.g., alkaline environments), it can be useful to limit the number ofhistidine residues in a polypeptide of the invention to no more than oneor two, or even none. In addition, because proline residues tend tointroduce kinks into secondary structure elements (e.g., α-helices andβ-strands), it can be useful exclude proline residues in the striapathicregion of a polypeptide of the invention, or limit their number to nomore than one.

Class I Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class Ipolypeptide. Class I polypeptides comprise, consist essentially of, orconsist of a striapathic region that includes a sequence selected fromthe group of sequences defined by Formula I:

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (Formula I).

Each of amino acid residues Y_(1a), Y_(1b), Y_(1c), Y_(2a), Y_(2b), andY_(2c) in Formula I can be selected from the group consisting of Phe(F), Trp (W), Tyr (Y), His (H), Leu (L), Cys (C), Met (M), Val (V), Ile(I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). In certainembodiments, at least 3, 4, 5, or 6 of amino acid residues Y_(1a),Y_(1b), Y_(1c), Y_(2a), Y_(2b), and Y_(2c) in Formula I are selectedfrom the group consisting of Phe (F), Trp (W), Tyr (Y), His (H), and Leu(L). In certain embodiments, at least 3, 4, 5, or 6 of amino acidresidues Y_(1a), Y_(1b), Y_(1c), Y_(2a), Y_(2b), and Y_(2c) in Formula Iare selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).In certain embodiments, less than two (and in certain embodiments 1 ornone) of amino acid residues Y_(1a), Y_(1b), Y_(1c), Y_(2a), Y_(2b), andY_(2c) in Formula I are selected from the group consisting of Pro (P),Thr (T), Ser (S), Ala (A), and Gly (G).

The module Y_(1a)-Y_(1b)-Y_(1c) in Formula I can have a sequenceselected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp(WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC),Met-Met-Met (MMM), Val-Val-Val (VVV), Ile-Ile-Ile (III). Alternatively,the module Y_(1a)-Y_(1b)-Y_(1c) in Formula I can have a sequenceselected from the group consisting of Pro-Pro-Pro (PPP), Thr-Thr-Thr(TTT), and Ala-Ala-Ala (AAA). In certain embodiments, moduleY_(1a)-Y_(1b)-Y_(1c) in Formula I has a sequence selected from the groupconsisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY),and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW),Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr(FYY), Tyr-Phe-Tyr (YFY), Tyr-Tyr-Phe (YYF), Trp-Trp-Tyr (WWY),Trp-Tyr-Tyr (WYY), Tyr-Trp-Tyr (YWY), Tyr-Tyr-Trp (YYW), Phe-Trp-Tyr(FWY), Phe-Tyr-Trp (FYW), Trp-Phe-Tyr (WFY), Trp-Tyr-Phe (WYF),Tyr-Trp-Phe (YWF), or Tyr-Phe-Trp (YFW)).

The module Y_(2a)-Y_(2b)-Y_(2c) in Formula I can have a sequenceselected from the group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp(WWW), Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC),Met-Met-Met (MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).Alternatively, the module Y_(2a)-Y_(2b)-Y_(2c) in Formula I can have asequence selected from the group consisting of Pro-Pro-Pro (PPP),Thr-Thr-Thr (TTT), and Ala-Ala-Ala (AAA). In certain embodiments, moduleY_(2a)-Y_(2b)-Y_(2c) in Formula I has a sequence selected from the groupconsisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY),and combinations thereof (e.g., Phe-Phe-Trp (FFW), Phe-Trp-Trp (FWW),Trp-Phe-Trp (WFW), Trp-Trp-Phe (WWF), Phe-Phe-Tyr (FFY), Phe-Tyr-Tyr(FYY), Tyr-Phe-Tyr (YFY), Tyr-Tyr-Phe (YYF), Trp-Trp-Tyr (WWY),Trp-Tyr-Tyr (WYY), Tyr-Trp-Tyr (YWY), Tyr-Tyr-Trp (YYW), Phe-Trp-Tyr(FWY), Phe-Tyr-Trp (FYW), Trp-Phe-Tyr (WFY), Trp-Tyr-Phe (WYF),Tyr-Trp-Phe (YWF), or Tyr-Phe-Trp (YFW)).

Thus, a Class I anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region having a sequenceselected from the group consisting of FFF-X_(1a)-FFF (SEQ ID NO: 1).WWW-X_(1a)-WWW (SEQ ID NO: 2), YYY-X_(1a)-YYY (SEQ ID NO: 3), andcombinations thereof. Alternatively, a Class I anti-inflammatorypolypeptide can comprise, consist essentially of, or consist of astriapathic region having a sequence selected from the group consistingof LLL-X_(1a)-LLL (SEQ ID NO: 4). CCC-X_(1a)-CCC (SEQ ID NO: 5),MMM-X_(1a)-MMM (SEQ ID NO: 6), VVV-X_(1a)-VVV (SEQ ID NO: 7), andIII-X_(1a)-III (SEQ ID NO: 8). In such peptides, X_(1a) can be selectedfrom the group consisting of Arg (R), His (H), and Lys (K); or X_(1a)can be selected from the group consisting of Glu (E), Gln (Q), Asn (N),and Asp (D).

A Class I anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region having a sequenceselected from the group of sequences defined by Formula II or the groupof sequences defined by Formula III:

Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)  (FormulaII);

X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaIII).

The Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c) sequences definedby Formulas II and III can be any of the sequences described above inconnection with Formula I. X_(2a) and X_(3a) in Formulas II and III canbe each individually selected from the group consisting of Arg (R), His(H), Lys (K), Glu (E), Gln (Q), Asn (N), and Asp (D). Alternatively,X_(2a) and X_(3a) in Formulas II and III can be each individuallyselected from the group consisting of Arg (R), His (H), and Lys (K). Inother alternatives, X_(2a) and X_(3a) in Formulas II and III can be eachindividually selected from the group consisting of Arg (R), His (H), Lys(K), and Gln (Q). In other alternatives, X_(2a) and X_(3a) in FormulasII and III can be each individually selected from the group consistingGlu (E), Gln (Q), Asn (N), and Asp (D). In other alternatives, X_(2a) inFormulas II and III can be selected from the group consisting of Arg(R), His (H), and Lys (K), and X_(3a) in Formulas II and III can beselected from the group consisting of Glu (E), Gln (Q), Asn (N), and Asp(D). Y3a in Formulas II and III can be selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val(V), and Ile (I). In certain embodiments, Y3a in Formulas II and III isselected from the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu(L).

The modules X_(2a)-Y_(3a)-X_(3a) in Formulas II and III can be selectedfrom the group consisting of EFQ, EFE, EFN, EFD, NFQ. NFE. NFN, NFD,QFQ, QFE, QFN, QFD, DFQ, DFE, DFN, DFD, EWQ, EWE, EWN, EWD, NWQ, NWE,NWN, NWD, QWQ, QWE, QWN, QWD, DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EYD,NYQ, NYE, NYN, NYD, QYQ, QYE, QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE,ELN, ELD, NLQ, NLE, NLN, NLD, QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD,RFR, RFQ, RFE, RFN, RFD, RWR, RWQ, RWE, RWN, and RWD.

A Class I anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region comprising,consisting essentially of, or consisting of a sequence selected from thegroup of sequences listed in Table 3, e.g., RP394, RP108-RP123,RP125-131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165,RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, RP273,RP280-281, and RP287. In certain embodiments, the Class Ianti-inflammatory polypeptide can comprise, consist essentially of, orconsist of a striapathic region that comprises, consists essentially of,or consists of a sequence selected from the group of sequencesconsisting of RP113 (SEQ ID NO: 39), RP118 (SEQ ID NO: 44), and RP394(SEQ ID NO: 33).

Class II Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class IIpolypeptide. Class II anti-inflammatory polypeptides can comprise,consist essentially of, or consist of a striapathic region that includesa sequence selected from the group of sequences defined by Formula VII:

Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (Formula VII).

Amino acid residue Y_(2a) in Formula VII can be selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val(V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). Incertain embodiments, amino acid residue Y_(2a) in Formula VII isselected from the group consisting of Phe (F), Trp (W), and Tyr (Y).Alternatively, amino acid residue Y_(2a) in Formula VII can be selectedfrom the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile(I).

Amino acid residue Y_(2b) in Formula VII can be selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val(V), Ile (I), Pro (P), Thr (T), Ser (S), Ala (A), and Gly (G). Incertain embodiments, amino acid residue Y_(2b) in Formula VII isselected from the group consisting of Phe (F), Trp (W), and Tyr (Y).Alternatively, amino acid residue Y_(2b) in Formula VII can be selectedfrom the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile(I).

Amino acid residue X_(1b) in Formula VII can be selected from the groupconsisting of Arg (R), Lys (K), and His (H). Alternatively amino acidresidue X_(1b) in Formula VII can be selected from the group consistingof Asn (N), Gln (Q), Asp (D), and Glu (E).

Amino acid residue X_(2a) in Formula VII can be selected from the groupconsisting of Arg (R), Lys (K), and His (H). Alternatively, amino acidresidue X_(2a) can be selected from the group consisting of Asn (N), Gln(Q), Asp (D), and Glu (E).

The sequence X_(1b)-Y_(2a)-Y_(2b)-X_(2a) in Formula VII can be selectedfrom the group consisting of Lys-Phe-Phe-Lys (KFFK; SEQ ID NO: 386),Lys-Trp-Trp-Lys (KWWK; SEQ ID NO: 387), Lys-Tyr-Try-Lys (KYYK; SEQ IDNO: 388), Lys-Phe-Trp-Lys (KFWK; SEQ ID NO: 389), Lys-Trp-Phe-Lys (KWFK;SEQ ID NO: 390), Lys-Phe-Tyr-Lys (KFYK; SEQ ID NO: 391), Lys-Tyr-Phe-Lys(KYFK; SEQ ID NO: 392), Lys-Trp-Tyr-Lys (KWYK; SEQ ID NO: 393), andLys-Tyr-Trp-Lys (KYWK; SEQ ID NO: 394). Alternatively, the sequenceX_(1b)-Y_(2a)-Y_(2b)-X_(2a) in Formula VII can be selected from thegroup consisting of Arg-Phe-Phe-Arg (RFFR; SEQ ID NO: 395),Arg-Trp-Trp-Arg (RWWR; SEQ ID NO: 396), Arg-Tyr-Try-Arg (RYYR; SEQ IDNO: 397), Arg-Phe-Trp-Arg (RFWR; SEQ ID NO: 398), Arg-Trp-Phe-Arg (RWFR;SEQ ID NO: 399), Arg-Phe-Tyr-Arg (RFYR; SEQ ID NO: 400), Arg-Tyr-Phe-Arg(RYFR; SEQ ID NO: 401), Arg-Trp-Tyr-Arg (RWYR; SEQ ID NO: 402), andArg-Tyr-Trp-Arg (RYWR; SEQ ID NO: 403). In other alternatives, thesequence X_(1b)-Y₂₂-Y_(2b)-X_(2a) in Formula VII can be selected fromthe group consisting of His-Phe-Phe-His (HFFH; SEQ ID NO: 404),His-Trp-Trp-His (HWWH; SEQ ID NO: 405), His-Tyr-Try-His (HYYH; SEQ IDNO: 406), His-Phe-Trp-His (HFWH; SEQ ID NO: 407), His-Trp-Phe-His (HWFH;SEQ ID NO: 408), His-Phe-Tyr-His (HFYH; SEQ ID NO: 409), His-Tyr-Phe-His(HYFH; SEQ ID NO: 410), His-Trp-Tyr-His (HWYH; SEQ ID NO: 411), andHis-Tyr-Trp-His (HYWH; SEQ ID NO:132).

Amino acid residue X_(1a) in Formula VII can be selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E). In certain embodiments, amino acid residue X_(1a) is selectedfrom the group consisting of Arg (R) and Gln (Q). In certainembodiments, amino acid residue X_(1a) in Formula VII is Arg (R).Alternatively, amino acid residue X_(1a) in Formula VII can be selectedfrom the group consisting of Lys (K), Gln (Q), Glu (E), and Asn (N).

Amino acid residue X_(2b) in Formula VII can be selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E). In certain embodiments, amino acid residue X_(2b) is selectedfrom the group consisting of Arg (R) and Gln (Q). In certainembodiments, amino acid residue X_(2b) in Formula VII is Arg (R).Alternatively, amino acid residue X_(2b) in Formula VII can be selectedfrom the group consisting of Lys (K), Gln (Q), Glu (E), and Asn (N).

Amino acid residue Y_(1a) in Formula VII can be selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val(V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). Incertain embodiments, amino acid residue Y_(1a) in Formula VII isselected from the group consisting of Phe (F), Trp (W), and Tyr (Y).Alternatively, amino acid residue Y_(1a) in Formula VII can be selectedfrom the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile(I).

Amino acid residue Y_(3a) in Formula VII can be selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val(V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G). Incertain embodiments, amino acid residue Y_(3a) in Formula VII isselected from the group consisting of Phe (F), Trp (W), and Tyr (Y).Alternatively, amino acid residue Y_(3a) in Formula VII can be selectedfrom the group consisting of Leu (L), Cys (C), Met (M), Val (V), Ile(I).

Thus, a Class II anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region having a sequenceselected from the group consisting of F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F(SEQ ID NO: 9), F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-W (SEQ ID NO: 10),W-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F (SEQ ID NO: 11),F-X_(1a)-X_(1b)-FW-X_(2a)-X_(2b)-F (SEQ ID NO: 12),F-X_(1a)-X_(1b)-WF-X_(2a)-X_(2b)-F (SEQ ID NO: 13),F-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-F (SEQ ID NO: 14),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-F (SEQ ID NO: 15),F-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 16),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 17),F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-Y (SEQ ID NO: 18),Y-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F (SEQ ID NO: 19),F-X_(1a)-X_(1b)-FY-X_(2a)-X_(2b)-F (SEQ ID NO: 20),F-X_(1a)-X_(1b)-YF-X_(2a)-X_(2b)-F (SEQ ID NO: 21),F-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-F (SEQ ID NO: 22),Y-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-F (SEQ ID NO: 23),F-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 24), andY-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 25),Y-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-W (SEQ ID NO: 26),W-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 27),Y-X_(1a)-X_(1b)-YW-X_(2a)-X_(2b)-Y (SEQ ID NO: 28),Y-X_(1a)-X_(1b)-WY-X_(2a)-X_(2b)-Y (SEQ ID NO: 29),Y-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-Y (SEQ ID NO: 30),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-Y (SEQ ID NO: 31), andY-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 32). Amino acid residuesX_(1a), X_(1b), X_(2a), and X_(2b) in the foregoing sequences can beselected as discussed above.

A Class II anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesa first additional amino acid residue directly bound to amino acidresidue Y_(1a) of Formula VII. The first additional amino acid residuecan be a hydrophobic amino acid residue (e.g., a residue selected fromthe group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met(M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G);a residue selected from the group consisting of Phe (F), Trp (W), andTyr (Y); a residue selected from the group consisting of Phe (F), Trp(W), Tyr (Y), and Leu (L); or, a residue selected from the groupconsisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)).Alternatively, the first additional amino acid residue can be ahydrophilic amino acid residue (e.g., a residue selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E); a residue selected from the group consisting of Arg (R), Lys(K), and His (H); a residue selected from the group consisting Arg (R),Lys (K), His (H), and Gln (Q); or a residue selected from the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E)).

A Class II anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesa first additional amino acid residue directly bound to amino acidresidue Y_(3a) of Formula VII. The first additional amino acid residuecan be a hydrophobic amino acid residue (e.g., a residue selected fromthe group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met(M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G);a residue selected from the group consisting of Phe (F), Trp (W), andTyr (Y); a residue selected from the group consisting of Phe (F), Trp(W), Tyr (Y), and Leu (L); or, a residue selected from the groupconsisting of Leu (L), Cys (C), Met (M), Val (V), and Ile (I)).Alternatively, the first additional amino acid residue can be ahydrophilic amino acid residue (e.g., a residue selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E); a residue selected from the group consisting of Arg (R), Lys(K), and His (H); a residue selected from the group consisting Arg (R),Lys (K), His (H), and Gln (Q); or a residue selected from the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E)).

A Class II anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesa first additional amino acid residue directly bound to amino acidresidue Y_(1a) of Formula VII and a second additional amino acid residedirectly bound to amino acid residue Y_(3a) of Formula VII. The firstadditional amino acid residue can be a hydrophobic amino acid residueand the second additional amino acid residue can be a hydrophilic aminoacid residue. Alternatively, the first additional amino acid residue canbe a hydrophilic amino acid residue and the second amino acid residuecan be a hydrophobic amino acid residue. Regardless, the additionalhydrophobic amino acid residue can be selected from the group consistingof Phe (F), Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile(I), Thr (T), Pro (P), Ser (S), Ala (A), and Gly (G); and in certainembodiments from the group consisting of Phe (F), Trp (W), and Tyr (Y);and in additional embodiments from the group consisting of Phe (F). Theadditional hydrophilic amino acid residue can be selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E); and in certain embodiments, a residue selected from the groupconsisting of Arg (R), Lys (K), and His (H); or a residue selected fromthe group consisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

A Class II anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region comprising,consisting essentially of, or consisting of a sequence selected from thegroup of sequences listed in Table 5, e.g., RP124, RP132, RP134, RP142,RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185, RP186, RP424, RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207, RP209,RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227, RP233-RP239,RP398, RP241-RP247, RP250-RP256, RP426, RP427, RP285, and RP387. Incertain embodiments, the Class II anti-inflammatory polypeptidecomprises, consists essentially of, or consists of a striapathic regioncomprising, consisting essentially of, or consisting of a sequenceselected from the group consisting of RP124 (SEQ ID NO: 106), RP166 (SEQID NO: 112), RP182 (SEQ ID NO: 121), and RP183 (SEQ ID NO: 122).

Class XII Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class XIIpolypeptide. Class XII anti-inflammatory polypeptides can comprise,consist essentially of, or consist of a striapathic region that includesa sequence selected from the group of sequences defined by Formula XLIX:

Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)  (Formula XLIX).

Amino acid residues Y_(1a), Y_(2a), and Y_(3a) of Formula XLIX can beeach independently selected from the group consisting of Phe (F), Trp(W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), Pro (P), Thr(T), Ser (S), Ala (A), and Gly (G). In certain embodiments, amino acidresidues Y_(1a), Y_(2a), and Y_(3a) of Formula XLIX are eachindependently selected from: the group consisting of Phe (F), Trp (W),and Tyr (Y); the group consisting of Phe (F), Trp (W), Tyr (Y), and Leu(L); or the group consisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile(I), Cys (C), Met (M), Val (V), and Ala (A).

Amino acid residues X_(1a), X_(2a), and X_(3a) of Formula XLIX can beeach independently selected from the group consisting of Arg (R), Lys(K), His (H), Gln (Q), Glu (E), Asn (N), and Asp (D). In certainembodiments, amino acid residues X_(1a), X_(2a), and X_(3a) are eachindependently selected from the group consisting of Arg (R), Lys (K),and His (H). Alternatively, amino acid residues X_(1a), X_(2a), andX_(3a) are each independently selected from the group consisting of Arg(R), Lys (K), His (H), and Gln (Q).

A Class XII anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesa first additional amino acid residue. The first additional amino acidresidue can be a hydrophilic amino acid residue directly bound to aminoacid residue Y_(1a) of Formula XLIX. Thus, the first additional aminoacid residue can be, for example, a residue selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E); a residue selected from the group consisting of Arg (R), Lys(K), and His (H); a residue selected from the group consisting Arg (R),Lys (K), His (H), and Gln (Q); or a residue selected from the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E)). Alternatively,the first amino acid residue can be a hydrophobic amino acid residuedirectly bound to amino acid residue X_(3a) of Formula XLIX. Thus, thefirst additional amino acid residue can be, for example, a residueselected from the group consisting of Phe (F), Trp (W), and Tyr (Y); aresidue selected from the group consisting of Phe (F), Trp (W), Tyr (Y),and Leu (L); or a residue selected from the group consisting of Phe (F),Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), and Ala(A)).

A Class XII anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesfirst and second additional amino acid residues. The first additionalamino acid residue can be a hydrophilic amino acid residue, as discussedabove, which is directly bound to amino acid residue Y_(1a) of FormulaXLIX. The second additional amino acid residue can be directly bound tothe first additional amino acid residue. Thus, the second additionalamino acid residue can be a hydrophobic amino acid residue, e.g., aresidue selected from the group consisting of Phe (F), Trp (W), Tyr (Y),Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S),Ala (A), and Gly (G); a residue selected from the group consisting ofPhe (F), Trp (W), and Tyr (Y); a residue selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residueselected from the group consisting of Leu (L), Cys (C), Met (M), Val(V), and Ile (I)). Alternatively, the second additional amino acidresidue can be a hydrophobic amino acid residue directly bound to aminoacid residue X_(3a) of Formula XLIX, as discussed above.

A Class XII anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesfirst, second, and third additional amino acid residues. The firstadditional amino acid residue can be a hydrophilic amino acid residuewhich is directly bound to amino acid residue Y_(1a) of Formula XLIX andthe second additional amino acid residue can be a hydrophobic amino acidresidue which is directly bound to the first additional amino acidresidue, as discussed above. The third additional amino acid residue canbe a hydrophilic amino acid residue that is directly bound to the secondadditional amino acid residue. Thus, the third additional amino acidresidue can be, for example, a residue selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E); a residue selected from the group consisting of Arg (R), Lys(K), and His (H); a residue selected from the group consisting Arg (R),Lys (K), His (H), and Gln (Q); or a residue selected from the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E)). Alternatively,the third amino acid residue can be a hydrophobic amino acid residuedirectly bound to amino acid residue X_(3a) of Formula XLIX. Thus, thethird additional amino acid residue can be, for example, a residueselected from the group consisting of Phe (F), Trp (W), and Tyr (Y); aresidue selected from the group consisting of Phe (F), Trp (W), Tyr (Y),and Leu (L); or a residue selected from the group consisting of Phe (F),Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), Met (M), Val (V), and Ala(A)).

A Class XII anti-inflammatory polypeptide can comprise, consistessentially of, or consist of a striapathic region that further includesfour, five, six, or more additional amino acid residues. The additionalamino acid residue can be added in a manner that continues thealternating patter of a hydrophobic amino acid residue followed by ahydrophilic amino acid residue followed by a hydrophobic amino acidresidue, as shown in Formula XLIX. In this manner, Class XIIanti-inflammatory polypeptides can be expanded to comprise, consistessentially of, or consist of a striapathic region having 10, 11, 12, ormore amino acid residues.

An anti-inflammatory polypeptide of Class XII can comprise, consistessentially of, or consist of a striapathic region comprising,consisting essentially of, or consisting of a sequence selected from thegroup consisting of RP393, RP391, PR392, RP390, and RP389.

Class XIV Polypeptides

An anti-inflammatory polypeptide of the invention can be a Class XIVpolypeptide. Class XIV anti-inflammatory polypeptides can comprise,consist essentially of, or consist of a striapathic region that includesa sequence selected from the group of sequences defined by any one ofFormulas LI through LIV:

X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-X_(2a)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)  (FormulaLI);

Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(1a)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)  (FormulaLII);

Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2b)-Y_(3a)-X_(3a)-Y_(4a)  (FormulaLIII); and

Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-Y_(3b)-Y_(3c)-X_(3a)-Y_(4a)-Y_(4b)  (FormulaLIV).

The striapathic region of a Class XIV polypeptide can include at least 3(e.g., 3 to 6) proline amino acid residues. For example, amino acidresidues Y_(1a), Y_(2a), and Y_(2b) in Formula LI can be proline aminoacid residues. Alternatively, amino acid residues Y_(1c), Y_(1d), andY_(2b) in Formula LII can be proline amino acid residues. In otheralternatives, amino acid residues Y_(1a), Y_(2a), Y_(2b), Y_(2c),Y_(3a), and Y_(4a) in Formula LIII can be proline amino acid residues.In still other alternatives, amino acid residues Y_(1a), Y_(2b), Y_(3a),Y_(3b), Y_(3c), and Y_(4b) in Formula LIV can be proline amino acidresidues.

Hydrophobic amino acid residues (e.g., Y_(1a), Y_(1b), Y_(1c), Y_(1d),Y_(2a), Y_(2b), Y_(2c), Y_(2d), Y_(3a), Y_(3b), Y_(3c), Y_(4a), andY_(4b)) not designated as proline residues in Formulas LI through LIVcan be each individually selected from the group consisting of Phe (F),Trp (W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T),Pro (P), Ser (S), Ala (A), and Gly (G). In certain embodiments, suchhydrophobic amino acid residues are each individually selected from: thegroup consisting of Phe (F), Trp (W), and Tyr (Y); the group consistingof Phe (F), Trp (W), Tyr (Y), and Leu (L); or, the group consisting ofLeu (L), Cys (C), Met (M), Val (V), and Ile (I)).

Hydrophilic amino acid residues in Formulas LI through LIV (e.g.,X_(1a), X_(1b), X_(2a), X_(2b), and X_(3a)) can be each individuallyselected from the group consisting of Arg (R), Lys (K), His (H), Asn(N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, suchhydrophilic amino acid residues are each individually selected from thegroup consisting of Arg (R), Lys (K), and His (H). Alternatively, suchhydrophilic amino acid residues are each individually selected from: thegroup consisting of Arg (R), Lys (K), His (H), and Gln (Q); or the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

An anti-inflammatory polypeptide of Class XIV can comprise, consistessentially of, or consist of a striapathic region that comprises,consists essentially of, or consists of a sequence selected from thegroup consisting of RP449, RP450, RP448, RP447, RP452, RP451, RP444,RP441, RP446, RP445, RP442, and RP443.

Other Classes of Polypeptides

An anti-inflammatory polypeptide of the invention can be from any ofClasses II through XI and XIII. Such anti-inflammatory polypeptides cancomprise, consist essentially of, or consist of a striapathic regionthat includes a sequence selected from the group of sequences defined byany one of Formulas IV through XLVIII and L.

Hydrophobic amino acid residues in Formulas IV through XLVIII and L(e.g., Y_(1a), Y_(1b), Y_(1c), Y_(1d), Y_(1e), Y_(2a), Y_(2b), Y_(2c),Y_(2d), Y_(2e), Y_(3a), Y_(3b), Y_(3c), Y_(4a) and Y_(4b)) can be eachindividually selected from the group consisting of Phe (F), Trp (W), Tyr(Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser(S), Ala (A), and Gly (G). In certain embodiments, such hydrophobicamino acid residues are each individually selected from: the groupconsisting of Phe (F), Trp (W), and Tyr (Y); the group consisting of Phe(F), Trp (W), Tyr (Y), and Leu (L); or, the group consisting of Leu (L),Cys (C), Met (M), Val (V), and Ile (I)).

Hydrophilic amino acid residues in Formulas IV through XLVIII and L(e.g., X_(1a), X_(1b), X_(1c), X_(1d), X_(2a), X_(2b), X_(2c), X_(2d),X_(3a), X_(3b), X_(3c), X_(4a), and X_(4b)) can be each individuallyselected from the group consisting of Arg (R), Lys (K), His (H), Asn(N), Gln (Q), Asp (D), and Glu (E). In certain embodiments, suchhydrophilic amino acid residues are each individually selected from thegroup consisting of Arg (R), Lys (K), and His (H). Alternatively, suchhydrophilic amino acid residues are each individually selected from: thegroup consisting of Arg (R), Lys (K), His (H), and Gln (Q); or the groupconsisting of Asn (N), Gln (Q), Asp (D), and Glu (E).

An anti-inflammatory polypeptide of any one of Formulas IV throughXLVIII and L can comprise, consist essentially of, or consist of astriapathic region that further includes a first additional amino acidresidue directly bound to the first amino acid residue of the Formula(e.g., Y_(1a) or X_(1a)) or to the last amino acid residue in theformula. The first additional amino acid residue can be a hydrophilicamino acid residue (e.g., a residue selected from the group consistingof Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E); aresidue selected from the group consisting of Arg (R), Lys (K), and His(H); a residue selected from the group consisting Arg (R), Lys (K), His(H), and Gln (Q); or a residue selected from the group consisting of Asn(N), Gln (Q), Asp (D), and Glu (E)). Alternatively, the first additionalamino acid residue can be a hydrophobic amino acid residue (e.g., aresidue selected from the group consisting of Phe (F), Trp (W), Tyr (Y),Leu (L), Cys (C), Met (M), Val (V), Ile (I), Thr (T), Pro (P), Ser (S),Ala (A), and Gly (G); a residue selected from the group consisting ofPhe (F), Trp (W), and Tyr (Y); a residue selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), and Leu (L); or, a residueselected from the group consisting of Leu (L), Cys (C), Met (M), Val(V), and Ile (I)).

An anti-inflammatory polypeptide of any one of Formulas IV throughXLVIII and L can comprise, consist essentially of, or consist of astriapathic region that further includes first and second additionalamino acid residues, with the first additional amino acid residuedirectly bound to the first amino acid residue of the Formula (e.g.,Y_(1a) or X_(1a)) or the last amino acid residue in the formula, and thesecond additional amino acid residue directly bound to the first aminoacid residue in the formula, the last amino acid residue in the formula,or the first additional amino acid residue. The first additional aminoacid residue can be a hydrophilic or hydrophobic amino acid residue, asdiscussed above. The second additional amino acid residue likewise canbe a hydrophilic or hydrophobic amino acid residue, as discussed above.

An anti-inflammatory polypeptide of any one of Formulas IV throughXLVIII and L can comprise, consist essentially of, or consist of astriapathic region that comprises, consists essentially of, or consistsof a sequence selected from the group consisting of RP396, RP405, RP174,RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189,RP388, RP417, RP191-RP193, RP404, RP196, RP397, RP197, RP402, RP203,RP409, RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240,RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP274,RP277-RP279, RP282, RP283, RP286, RP289, and RP414.

Variant Polypeptides

The exemplary anti-inflammatory polypeptide sequences shown in Tables3-9 (below) are merely examples and are not the only anti-inflammatorypolypeptides provided herein. Indeed, fragments and variants of thesequences of the disclosed peptides are within the scope of theinvention.

A “fragment” of the invention includes at least 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 contiguous amino acidresidues of a polypeptide disclosed herein (or up to one less than thenumber of amino acid residues in the subject polypeptide) and retains atleast one anti-inflammatory property of the subject polypeptide. Thus,fragments of the invention include polypeptides that are missing one,two, three, four, or more amino acids from the N-terminus and/or theC-terminus relative to a polypeptide disclosed herein.

A “variant” of the invention is a polypeptide that is substantiallysimilar to a polypeptide disclosed herein and retains at least oneanti-inflammatory property of the subject polypeptide. Variants caninclude deletions (i.e., truncations) of one or more amino acid residuesat the N-terminus or the C-terminus of a subject polypeptide disclosedherein; deletion and/or addition of one or more amino acid residues atone or more internal sites in the subject polypeptide disclosed herein;and/or substitution of one or more amino acid residues at one or morepositions in the subject polypeptide disclosed herein. For subjectpolypeptides that are 12 amino acid residues in length or shorter,variant polypeptides can include three or fewer (e.g., two, one, ornone) deleted amino acid residues, whether located internally, at theN-terminal end, and/or at the C-terminal end.

Accordingly, the invention further provides anti-inflammatorypolypeptides that are at least 50% identical (e.g., at least 60%, 70%,80%, 90%, or more) to any one of the anti-inflammatory polypeptidesdisclosed in Tables 3-9 and still retain at least one anti-inflammatoryproperty. For example, the invention provides anti-inflammatorypolypeptides that are 3 to 24 amino acids residues in length andcomprise, consist essentially of, or consist of a striapathic regionsharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%, ormore identity) with a Class I anti-inflammatory polypeptide (e.g., anyone of the sequences of Table 3). Such identity can be shared, forexample, with RP-394 (SEQ ID NO: 33), RP-108 (SEQ ID NO: 34), RP-113(SEQ ID NO: 39), RP-118 (SEQ ID NO: 44), RP-129 (SEQ ID NO: 54), orRP-179 (SEQ ID NO: 86). Alternatively, the invention providesanti-inflammatory polypeptides that are 3 to 24 amino acid residues inlength and comprise, consist essentially of, or consist of a striapathicregion sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%,or more identity) with a Class II, Sub-class 1 anti-inflammatorypolypeptide (e.g., any one of the sequences of Table 5). Such identitycan be shared, for example, with RP-124 (SEQ ID NO: 106), RP-134 (SEQ IDNO: 108), RP-166 (SEQ ID NO: 112), RP-168 (SEQ ID NO: 114), RP-182 (SEQID NO: 121), or RP-183 (SEQ ID NO: 122). In other alternatives, theinvention provides anti-inflammatory polypeptides that are 3 to 24 aminoacid residues in length and comprise, consist essentially of, or consistof a striapathic region sharing at least 50% identity (e.g., at least60%, 70%, 80%, 90%, or more identity) with any Class II through Class IXor Class XIII anti-inflammatory polypeptide (e.g., any one of thesequences of Table 6). In other alternatives, the invention providesanti-inflammatory polypeptides that are 3 to 24 amino acid residues inlength and comprise, consist essentially of, or consist of a striapathicregion sharing at least 50% identity (e.g., at least 60%, 70%, 80%, 90%,or more identity) with any Class VIII to Class XI anti-inflammatorypolypeptide (e.g., any one of the sequences of Table 7). In otheralternatives, the invention provides anti-inflammatory polypeptides thatare 3 to 24 amino acid residues in length and comprise, consistessentially of, or consist of a striapathic region sharing at least 50%identity (e.g., at least 60%, 70%, 80%, 90%, or more identity) with aClass XII or Class XIV anti-inflammatory polypeptide (e.g., any one ofthe sequences of Table 8). In still other alternatives, the inventionprovides anti-inflammatory polypeptides that are 3 to 24 amino acidresidues in length and comprise, consist essentially of, or consist of astriapathic region sharing at least 50% identity (e.g., at least 60%,70%, 80%, 90%, or more identity) with any one of the combinationsequences of Table 9.

The differences between the striapathic region of a homologousanti-inflammatory polypeptide and any one of the anti-inflammatorypolypeptides of Tables 3-9 can include deletions, additions, and/orsubstitutions of amino acid residues, as discussed above. Substitutedamino acid residues can be unrelated to the amino acid residue beingreplaced (e.g., unrelated in terms or hydrophobicity/hydrophilicity,size, charge, polarity, etc.), or the substituted amino acid residuescan constitute similar, conservative, or highly conservative amino acidsubstitutions. As used herein. “similar,” “conservative,” and “highlyconservative” amino acid substitutions are defined as shown in Table 2,below. The determination of whether an amino acid residue substitutionis similar, conservative, or highly conservative is based exclusively onthe side chain of the amino acid residue and not the peptide backbone,which may be modified to increase peptide stability, as discussed below.

TABLE 2 Classification of Amino Acid Substitutions Highly SimilarConservative Conservative Amino Acid in Amino Acid Amino Acid Amino AcidSubject Polypeptide Substitutions Substitutions Substitutions Glycine(G) A, S, N A n/a Alanine (A) S, G, T, V, C, P, Q S, G, T S Serine (S)T, A, N, G, Q T, A, N T, A Threonine (T) S, A, V, N, M S, A, V, N SCysteine (C) A, S, T, V, I A n/a Proline (P) A, S, T, K A n/a Methionine(M) L, I, V, F L, I, V L, I Valine (V) I, L, M, T, A I, L, M I Leucine(L) M, I, V, F, T, A M, I, V, F M, I Isoleucine (I) V, L, M, F, T, C V,L, M, F V, L, M Phenylalanine (F) W, L, M, I, V W, L n/a Tyrosine (Y) F,W, H, L, I F, W F Tryptophan (W) F, L, V F n/a Asparagine (N) Q Q QGlutamine (Q) N N N Aspartic Acid (D) E E E Glutamic Acid (E) D D DHistidine (H) R, K R, K R, K Lysine (K) R, H R, H R, H Arginine (R) KHK, H K, H

In certain embodiments, a variant polypeptide of the invention binds totwo or more targets (e.g., pro-inflammatory targets). In someembodiments, a variant polypeptide binds to three, four, five, or morepro-inflammatory targets. For example, a variant polypeptide can bind toany combination of targets disclosed herein (e.g., an NF-kB Class IIprotein and human serum albumin (HSA)), as discussed below. Such bindingcan be based on in silico, in vitro, or in vivo data.

Modeling Polypeptide Binding to Target Molecules

The determination of whether a polypeptide has anti-inflammatoryproperties can be performed in silico. For example, the binding of apolypeptide (e.g., a polypeptide that has a length of 3 to 24 amino acidresidues and includes a striapathic region comprising at least 25% ofthe length of the polypeptide) to a putative target molecule can bemodeled in silico, using any of the numerous molecular modeling anddocking platforms available in the art, to thereby assess whether thepolypeptide is an anti-inflammatory polypeptide. The on-line ClusPro™algorithm, version 2.0 (developed at Boston University) is particularlyuseful for modeling the conformation of polypeptides and their bindingto target molecules, such as signaling proteins, as described in theExamples set forth below. Modeling algorithms, such as the ClusPro™algorithm, that allow for docking of polypeptides on target moleculescan be used, for example, to predict the binding energy associated withthe polypeptide-target interaction. Such predictions provide reasonableestimates for the binding energies, but they are not necessarily equalto the binding energies that would be calculated by testing thepolypeptides and protein targets in vitro. In that regard, the bindingenergies identified herein were all generated using the ClusPro™algorithm. Accordingly, absent indication to the contrary, any numericalreference to the binding energy associated with a peptide binding to aparticular target is a reference to a binding energy determined bymodeling the interaction using the ClusPro™ algorithm.

As detailed in the Examples below, the exemplary RP peptides have beenshown to interact with various signaling molecules associated withinflammation, including NF-kB Class II subunit RelB. TGFβ, Notch1,Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, as well as other membraneassociated signaling molecules, including CD206, CD47 and SIRP-α,translational modification protein transglutaminase 2 (TGM2), andhistone modification enzyme histone methyl transferase (HMT). Uponfolding of these protein targets to their normal 3-dimensionalconformations, an amphipathic cleft is often generated that has highaffinity for the immune-modulating peptides herein described.

For modeling interactions between potential anti-inflammatorypolypeptides and NF-kB Class II subunits, any Class II subunit sequencecan be used (e.g., RelA, RelB, cRel, NF-kB1, or NF-kB2). In certainembodiments, the Class II subunit sequence folds into a functional ClassII subunit or a functional fragment thereof. The particular Class IIsubunit used for modeling can be selected based on the type of subjectthat the anti-inflammatory polypeptide is intended to treat (e.g., ahuman NF-kB Class II subunit is selected if the intended subject is ahuman, a bovine NF-kB Class II subunit is selected if the intendedsubject is a cow, etc.). The NF-kB Class II subunit sequence used formodeling can be the human RelB sequence (NCBI Accession No. NP-006500),which is as follows:

(SEQ ID NO: 367)MLRSGPASGPSVPTGRAMPSRRVARPPAAPELGALGSPDLSSLSLAVSRSTDELEIIDEYIKENGFGLDGGQPGPGEGLPRLVSRGAASLSTVTLGPVAPPATPPPWGCPLGRLVSPAPGPGPQPHLVITEQPKQRGMRFRYECEGRSAGSILGESSTEASKTLPAIELRDCGGLREVEVTACLVWKDWPHRVHPHSLVGKDCTDGICRVRLRPHVSPRHSFNNLGIQCVRKKEIEAAIERKIQLGIDPYNAGSLKNHQE

EPLPFTYLPRDHDSYGVDKKRKRGMPDVLGELNSSDPHGIESKRRKKKPAILDHFLPNHGSGPFLPPSALLPDPDFFSGTVSLPGLEPPGGPDLLDDGFAYDPTAPTLFTMLDLLPPAPPHASAVVCSGGAGAVVGETPGPEPLTLDSYQAPGPGDGGTASLVGSNMFPNHYREAAFGGGLLSPGPEAT.

The underlined sequence in human RelB (above) has been identified as thedimerization domain. The highlighted amino acid residues (Tyr-300,Leu-302, and His-332) are believed to be particularly important in thedimerization interaction.

An anti-inflammatory polypeptide can be identified based on its abilityto bind (e.g., in silico) to the dimerization pocket of the Class IIsubunit and/or interfere with or block the ability of the Class IIsubunit to dimerize. For example, the anti-inflammatory polypeptide canbind to at least one amino acid residue of human RelB (SEQ ID NO: 367)selected from the group consisting of Leu-281, Ile-283, Cys-284,Glu-298, Tyr-300, Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329,Asp-330, Val-331, His-332, Gln-334, and Leu-371, or the equivalent aminoacid residue(s) in a different human NF-kB Class 11 protein or an NF-kBClass II protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human RelB (SEQ ID NO: 367) selected from the groupconsisting of Glu-298, Tyr-300, Leu-302, Asp-330, Gln-334, and Leu-371or the equivalent amino acid residue(s) in a different human NF-kB ClassII protein or an NF-kB Class II protein of another species.

In certain embodiments, an anti-inflammatory polypeptide binds to humanRelB (SEQ ID NO: 367) with an affinity of at least −650 kcal/mol, and incertain embodiments at least −700, −750, −800, −850, −900, −925, −950,−975, −1000, −1025, −1050, −1075, −1100, −1125, −1150, −1200 kcal/mol,or greater. The requisite binding affinity can correspond to a bindingaffinity that can be detected in vitro or in vivo. Alternatively, therequisite binding affinity can correspond to a binding affinity that canbe detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and TGFβ, any TGFβ protein sequence can be used. The TGFβsequence generally folds into a functional TGFβ protein or a functionalfragment thereof. The TGFβ protein sequence used for modeling can beselected based on the type of subject that the anti-inflammatorypolypeptide is intended to treat (e.g., a human TGFβ is selected if theintended subject is a human, a bovine TGFβ is selected if the intendedsubject is a cow, etc.). The sequence used for modeling can be the humanTGFβ sequence (NCBI Acc. No. NP_000651.3), which is as follows:

(SEQ ID NO: 368) MPPSGLRLLPLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSELREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSNRLLAPSDSPEWLSFDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLATIHGMNRPFLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the receptor binding site on TGFβ and/orinterfere with or block the ability of TGFβ to bind to its receptor. Forexample, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of human TGFβ (SEQ ID NO: 368) selected from thegroup consisting of Arg-25, Gly-29, Trp-30, Lys-31, Trp-32, Ile-33,His-34, Tyr-91, Val-92, Val-93, Gly-94, Arg-95, Lys-96, and Pro-97, orthe equivalent amino acid residue(s) in a TGFβ protein of anotherspecies. Alternatively, the anti-inflammatory polypeptide can bind to atleast one amino acid residue of human TGFβ (SEQ ID NO: 368) selectedfrom the group consisting of Leu-20, Ile-22, Phe-24, Asp-27, Leu-28,Trp-30, Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101 and Ser-112, orthe equivalent amino acid residue(s) in a TGFβ protein of anotherspecies. In other alternatives, the anti-inflammatory polypeptide canbind to at least one amino acid residue of human TGFβ (SEQ ID NO: 368)selected from the group consisting of Asp-27, Leu-28, Trp-30, andTrp-32, or the equivalent amino acid residue(s) in a TGFβ protein ofanother species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman TGFβ (SEQ ID NO: 368) with an affinity of at least −650 kcal/mol,and in certain embodiments at least −700, −750, −800, −850, −900, −925,−950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisitebinding affinity can correspond to a binding affinity that can bedetected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and Notch1, any Notch1 protein sequence can be used. TheNotch1 sequence used for modeling generally folds into a functionalNotch1 protein or a calcium-binding fragment thereof. The Notch1sequence used for modeling can be selected based on the type of subjectthat the anti-inflammatory polypeptide is intended to treat (e.g., ahuman Notch1 is selected if the intended subject is a human, a bovineNotch1 is selected if the intended subject is a cow, etc.). The sequenceused for modeling can be the human Notch1 sequence (GenBank Acc. No.AAG33848.1), which is as follows:

(SEQ ID NO: 369) MPPLLAPLLCLALLPALAARGPRCSQPGETCLNGGKCEAANGTEACVCGGAFVGPRCQDPNPCLSTPCKNAGTCHVVDRRGVADYACSCALGFSGPLCLTPLDNACLTNPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFEASYICHCPPSFHGPTCRQDVNECGQKPRLCRHGGTCHNEVGSYRCVCRATHTGPNCERPYVPCSPSPCQNGGTCRPTGDVTHECACLPGFTGQNCEENIDDCPGNNCKNGGACVDGVNTYNCPCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNTHGGYNCVCVNGWTGEDCSENIDDCASAACFHGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECSLGANPCEHAGKCINTLGSFECQCLQGYTGPRCEIDVNECVSNPCQNDATCLDQIGEFQCMCMPGYEGVHCEVNTDECASSPCLHNGRCLDKINEFQCECPTGFTGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGSCKDGVATFTCLCRPGYTGHHCETNINECSSQPCRLRGTCQDPDNAYLCFCLKGTTGPNCEINLDDCASSPCDSGTCLDKIDGYECACEPGYTGSMCNSNIDECAGNPCHNGGTCEDGINGFTCRCPEGYHDPTCLSEVNECNSNPCVHGACRDSLNGYKCDCDPGWSGTNCDINNNECESNPCVNGGTCKDMTSGIVCTCREGFSGPNCQTNINECASNPCLNKGTCIDDVAGYKCNCLLPYTGATCEWLAPCAPSPCRNGGECRQSEDYESFSCVCPTAGAKGQTCEVDINECVLSPCRHGASCQNTHGXYRCHCQAGYSGRNCETDIDDCRPNPCHNGGSCTDGINTAFCDCLPGFRGTFCEEDINECASDPCRNGANCTDCVDSYTCTCPAGFSGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQHVVNECDSRPCLLGGTCQDGRGLHRCTCPQGYTGPNCQNLVHWCDSSPCKNGGKCWQTHTQYRCECPSGWTGLYCDVPSVSCEVAAQRQGVDVARLCQHGGLCVDAGNTHHCRCQAGYTGSYCEDLVDECSPSPCQNGATCTDYLGGYSCKCVAGYHGVNCSEEIDECLSHPCQNGGTCLDLPNTYKCSCPRGTQGVHCEINVDDCNPPVDPVSRSPKCFNNGTCVDQVGGYSCTCPPGFVGERCEGDVNECLSNPCDARGTQNCVQRVNDFHCECRAGHTGRRCESVINGCKGKPCKNGGTCAVASNTARGFICKCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGPFTGPECQFPASSPCLGGNPCYNQGTCEPTSESPFYRCLCPAKFNGLLCHILDYSFGGGAGRDIPPPLIEEACELPECQEDAGNKVCSLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQRAEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVVVVLMPPEQLRNSSFHFLRELSRVLHTNVVFKRDAHGQQMIFPYYGREEELRKHPIKRAAEGWAAPDALLGQVKASLLPGGSEGGRRRRELDPMDVRGSIVYLEIDNRQCVQASSQCFQSATDVAAFLGALASLGSLNIPYKIEAVQSETVEPPPPAQLHFMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDAADLRMSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILIRNRATDLDARMHDGTTPLILAARLAVEGMLEDLINSHADVNAVDDLGKSALHWAAAVNNVDAAVVLLKNGANKDMQNNREETPLFLAAREGSYETAKVLLDHFANRDITDHMDRLPRDIAQERMHHDIVRLLDEYNLVRSPQLHGAPLGGTPTLSPPLCSPNGYLGSLKPGVQGKKVRKPSSKGLACGSKEAKDLKARRKKSQDGKGCLLDSSGMLSPVDSLESPHGYLSDVASPPLLPSPFQQSPSVPLNHLPGMPDTHLGIGHLNVAAKPEMAALGGGGRLAFETGPPRLSHLPVASGTSTVLGSSSGGALNFTVGGSTSLNGQCEWLSRLQSGMVPNQYNPLRGSVAPGPLSTQAPSLQHGMVGPLHSSLAASALSQMMSYQGLPSTRLATQPHLVQTQQVQPQNLQMQQQNLQPANIQQQQSLQPPPPPPQPHLGVSSAASGHLGRSFLSGEPSQADVQPLGPSSLAVHTILPQESPALPTSLPSSLVPPVTAAQFLTPPSQHSYSSPVDNTPSHQLQVPEHPFLTPSPESPDQWSSSSPHSNVSDWSEGVSSPPTSMQSQIARI PEAFK.

An anti-inflammatory polypeptide can be identified based on its abilityto bind to the calcium-binding site on Notch1 and/or interfere with orblock the ability of Notch1 to bind to calcium. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human Notch1 (SEQ ID NO: 369) selected from the groupconsisting of Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553,Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686,Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or the equivalent amino acidresidue(s) in a Notch1 protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human Notch1 (SEQ ID NO: 369) selected from the groupconsisting of Phe-1520, Trp-1557, Cys-1562, and Phe-1703, or theequivalent amino acid residue(s) in a Notch1 protein of another species.

In certain embodiments, a polypeptide of the invention binds to humanNotch1 (SEQ ID NO: 369) with an affinity of at least −650 kcal/mol, andin certain embodiments at least −700, −750, −800, −850, −900, −925,−950, −975, −1000, −1025, −1050, −1075 kcal/mol, or greater. Therequisite binding affinity can correspond to a binding affinity that canbe detected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and Wnt8R, any Wnt8R protein sequence can be used. TheWnt8R sequence used for modeling generally folds into a functional Wnt8Rprotein or a Wnt8-binding fragment thereof. The Wnt8R protein sequenceused for modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human Wnt8Ris selected if the intended subject is a human, a bovine Wnt8R isselected if the intended subject is a cow, etc.). The sequence used formodeling can be, for example, the bovine Wnt8R sequence (NCBI Acc. No.XP_005214377.1), which is as follows:

(SEQ ID NO: 370) MEWGYLLEVTSLLAALALLQRSSGAAAASAKELACQEITVPLCKGIGYNYTYMPNQFNHDTQDEAGLEVHQFWPLVEIQCSPDLKFFLCSMYTPICLEDYKKPLPPCRSVCERAKAGCAPLMRQYGFAWPDRMRCDRLPEQGNPDTLCMDYNRTDLTTAASSVDGDPVAGICYVGNQSLDNLLGFVLAPLVIYLFIGTMFLLAGFVSLFRIRSVIKQQGGPTKTHKLEKLMIRLGLFTVLYTVPAAVVVACLFYEQHNRPRWEATHNCPCLRDQPDQARRPDYAVFMLKYFMCLVVGITSGVWVWSGKTLESWRALCTRCCWASKGAGAAGAGAAGGGPGGGGPGAGGGGGPGAGGAGSLYSDVSTGLTWRSGTASSVSYPKQMPLSQV.

An anti-inflammatory polypeptide can be identified based on its abilityto bind to a Wnt ligand-binding site on Wnt8R and/or interfere with orblock the ability of Wnt8R to bind to a Wnt ligand (e.g., Wnt8). Forexample, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected from thegroup consisting of Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100,Lys-101, Pro-103, Pro-105, Pro-106, Arg-137 and Asp-145, or theequivalent amino acid residue(s) in a Wnt8R protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of bovine Wnt8R (SEQ ID NO: 370) selected fromthe group consisting of Tyr-52, Phe-57, Tyr-100, and Asp-145, or theequivalent amino acid residue(s) in a Wnt8R protein of another species.

In certain embodiments, a polypeptide of the invention binds to bovineWnt8R (SEQ ID NO: 370) with an affinity of at least −600 kcal/mol, andin certain embodiments at least −650, −700, −750, −800, −850, −875,−900, −925, −950, −975 kcal/mol, or greater. The requisite bindingaffinity can correspond to a binding affinity that can be detected invitro or in vivo. Alternatively, the requisite binding affinity cancorrespond to a binding affinity that can be detected in silico, e.g.,using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and TRAIL, any TRAIL protein sequence can be used. TheTRAIL sequence used for modeling in certain embodiments folds into afunction TRAIL protein or a functional fragment thereof. The TRAILprotein sequence used for modeling can be selected based on the type ofsubject that the anti-inflammatory polypeptide is intended to treat(e.g., a human TRAIL is selected if the intended subject is a human, abovine TRAIL is selected if the intended subject is a cow, etc.). Thesequence used for modeling can be the human TRAIL sequence (GenBank Acc.No. EAW78466.1), which is as follows:

(SEQ ID NO: 371) KEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the receptor binding site on TRAIL and/orinterfere with or block the ability of TRAIL to bind to its receptor.For example, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of human TRAIL (SEQ ID NO: 371) selected from thegroup consisting of Arg-130, Arg-158, Ser-159, Gly-160, His-161,Phe-163, Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239,Asp-267, Asp-269, His-270, and Glu-271, or the equivalent amino acidresidue(s) in a TRAIL protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human TRAIL (SEQ ID NO: 371) selected from the groupconsisting of Ala-123, His-161, Ser-162, Phe-163, Tyr-183, Tyr-185,Tyr-243, His-270, Glu-271, Phe-274, Phe-278, Leu-279, and Val-280, orthe equivalent amino acid residue(s) in a TRAIL protein of anotherspecies. In other alternatives, the anti-inflammatory polypeptide canbind to at least one amino acid residue of human TRAIL (SEQ ID NO: 371)selected from the group consisting of Phe-163, Tyr-243, Glu-271, andPhe-278, or the equivalent amino acid residue(s) in a TRAIL protein ofanother species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman TRAIL (SEQ ID NO: 371) with an affinity of at least −650 kcal/mol,and in certain embodiments at least −700, −750, −800, −850, −900, −925,−950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisitebinding affinity can correspond to a binding affinity that can bedetected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and IL6R, any IL6R protein sequence can be used. The IL6Rsequence used for modeling generally folds into a functional IL6Rprotein or a IL6-binding fragment thereof. The IL6R protein sequenceused for modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human IL6Ris selected if the intended subject is a human, a bovine IL6R isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human IL6R sequence (NCBI Acc. No. NP_786943.1),which is as follows:

(SEQ ID NO: 372) MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDNIASF.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the IL6-binding site on IL6R and/or interferewith or block the ability of IL6R to bind to its ligand, IL6. Forexample, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of human IL6R (SEQ ID NO: 372) selected from thegroup consisting of Glu-163, Gly-164, Phe-168, Gln-190, Phe-229,Tyr-230, Phe-279 and Gln-281, or the equivalent amino acid residue(s) ina IL6R protein of another species. Alternatively, the anti-inflammatorypolypeptide can bind to at least one amino acid residue of human IL6R(SEQ ID NO: 372) selected from the group consisting of Leu-108, Glu-140,Pro-162, Phe-229, Tyr-230, and Phe-279, or the equivalent amino acidresidue(s) in a IL6R protein of another species. In other alternatives,the anti-inflammatory polypeptide can bind to at least one amino acidresidue of human IL6R (SEQ ID NO: 372) selected from the groupconsisting of Glu-140, Phe-229, Tyr-230, Phe-279, or the equivalentamino acid residue(s) in a IL6R protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman IL6R (SEQ ID NO: 372) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. Therequisite binding affinity can correspond to a binding affinity that canbe detected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and IL10R, any appropriate IL10R protein sequence can beused. The IL10R sequence used for modeling generally folds into afunctional IL10R protein or a IL10-binding fragment thereof. The IL10Rprotein sequence used for modeling can be selected based on the type ofsubject that the anti-inflammatory polypeptide is intended to treat(e.g., a human IL10R is selected if the intended subject is a human, abovine IL10R is selected if the intended subject is a cow, etc.). Thesequence used for modeling can be the human IL10R sequence (NCBI Acc.No. NP_001549.2), which is as follows:

(SEQ ID NO: 373) MLPCLVVLLAALLSLRLGSDAHGTELPSPPSVWFEAEFFHHILHWTPIPNQSESTCYEVALLRYGIESWNSISNCSQTLSYDLTAVTLDLYHSNGYRARVRAVDGSRHSNWTVTNTRFSVDEVTLTVGSVNLEIHNGFILGKIQLPRPKMAPANDTYESIFSHFREYEIAIRKVPGNFTFTHKKVKHENFSLLTSGEVGEFCVQVKPSVASRSNKGMWSKEECISLTRQYFTVTNVIIFFAFVLLLSGALAYCLALQLYVRRRKKLPSVLLFKKPSPFIFISQRPSPETQDTIHPLDEEAFLKVSPELKNLDLHGSTDSGFGSTKPSLQTEEPQFLLPDPHPQADRTLGNREPPVLGDSCSSGSSNSTDSGICLQEPSLSPSTGPTWEQQVGSNSRGQDDSGIDLVQNSEGRAGDTQGGSALGHHSPPEPEVPGEEDPAAVAFQGYLRQTRCAEEKATKTGCLEEESPLTDGLGPKFGRCLVDEAGLHPPALAKGYLKQDPLEMTLASSGAPTGQWNQPTEEWSLLALSSCSDLGISDWSFAHDLAPLGCVAAPGGLLGSFNSDLVTLPLISSLQSSE.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the IL10-binding site on IL10R and/orinterfere with or block the ability of IL10R to bind to its ligand,IL10. For example, the anti-inflammatory polypeptide can bind to atleast one amino acid residue of human IL10R (SEQ ID NO: 373) selectedfrom the group consisting of Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73,Arg-76, Asn-94, Arg-96. Phe-143, Ala-189, Ser-190, and Ser-191, or theequivalent amino acid residue(s) in a IL6R protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of human IL10R (SEQ ID NO: 373) selected from thegroup consisting of Leu-41, Arg-42, Tyr-43, Ile-45, Glu-46, Ser-47,Trp-48, Arg-76, and Arg-78, or the equivalent amino acid residue(s) in aIL10R protein of another species. In other alternatives, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human IL10R (SEQ ID NO: 373) selected from the groupconsisting of Tyr-43, Ile-45, Glu-46, Trp-48, or the equivalent aminoacid residue(s) in a IL10R protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman IL10R (SEQ ID NO: 373) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −775, −800, −825,−850, −875, −900 kcal/mol, or greater. The requisite binding affinitycan correspond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and EGFR, any EGFR protein sequence can be used. The EGFRsequence used for modeling generally folds into a functional EGFRprotein or a ligand-binding fragment thereof. The EGFR protein sequenceused for modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human EGFRis selected if the intended subject is a human, a bovine EGFR isselected if the intended subject is a cow, etc.). Alternatively, thesequence used for modeling can be the drosophila EGFR sequence (GenBankAcc. No. AAR85273.1), which is as follows:

(SEQ ID NO: 374) KICIGTKSRLSVPSNKEHHYRNLRDRYTNCTYVDGNLELTWLPNENLDLSFLDNIREVTGYILISHVDVKKVVFPKLQIIRGRTLFSLSVEEEKYALFVTYSKMYTLEIPDLRDVLNGQVGFHNNYNLCHMRTIQWSEIVSNGTDAYYNYDFTAPERECPKCHESCTHGCWGEGPKNCQKFSKLTCSPQCAGGRCYGPKPRECCHLFCAGGCTGPTQKDCIACKNFFDEGVCKEECPPMRKYNPTTYVLETNPEGKYAYGATCVKECPGHLLRDNGACVRSCPQDKMDKGGECVPCNGPCPKTCPGVTVLHAGNIDSFRNCTVIDGNIRILDQTFSGFQDVYANYTMGPRYIPLDPERLEVFSTVKEITGYLNIEGTHPQFRNLSYFRNLETIHGRQLMESMFAALAIVKSSLYSLEMRNLKQISSGSWIQHNRDLCYVSNIRWPAIQKEPEQKVWVNENLRADLCEKNGTICSDQCNEDGCWGAGTDQCLNCKNFNFNGTCIADCGYISNAYKFDNRTCKICHPECRTCNGAGADHCQECVHVRDGQHCVSECPKNKYNDRGVCRECHATCDGCTGPKDTIGIGACTTCNLAIINNDATVKRCLLKDDKCPDGYFWEYVHPQEQGSLKPLAGRAVCRKCHPLCELCTNY GYHEQ.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the ligand-binding site on EGFR and/orinterfere with or block the ability of at least one ligand to bind toEGFR. For example, the anti-inflammatory polypeptide can bind to atleast one amino acid residue of drosophila EGFR (SEQ ID NO: 374)selected from the group consisting of Leu-10, Thr-40, Trp-41, Asp-48,Phe-51, Leu-63, His-66, Asp-68, Leu-88, and Tyr-101, or the equivalentamino acid residue(s) in a EGFR protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of drosophila EGFR (SEQ ID NO: 374) selected fromthe group consisting of Trp-41, Asp-48, Phe-51, Asp-68, and Tyr-101, orthe equivalent amino acid residue(s) in a EGFR protein of anotherspecies.

In certain embodiments, an anti-inflammatory polypeptide can bind todrosophila EGFR (SEQ ID NO: 374) with an affinity of at least −650kcal/mol, and in certain embodiments at least −700, −750, −800, −850,−900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. Therequisite binding affinity can correspond to a binding affinity that canbe detected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and CDK6, any CDK6 protein sequence can be used. The CDK6sequence used for modeling generally folds into a functional CDK6protein or a functional fragment thereof. The CDK6 protein sequence usedfor modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human CDK6is selected if the intended subject is a human, a bovine CDK6 isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human CDK6 sequence (NCBI Acc. No. NP_001250.1),which is as follows:

(SEQ ID NO: 375) MEKDGLCRADQQYECVAEIGEGAYGKVFKARDLKNGGRFVALKRVRVQTGEEGMPLSTIREVAVLRHLETFEHPNVVRLFDVCTVSRTDRETKLTLVFEHVDQDLTTYLDKVPEPGVPTETIKDMMFQLLRGLDFLHSHRVVHRDLKPQNILVTSSGQIKLADFGLARIYSFQMALTSVVVTLWYRAPEVLLQSSYATPVDLWSVGCIFAEMFRRKPLFRGSSDVDQLGKILDVIGLPGEEDWPRDVALPRQAFHSKSAQPIEKFVTDIDELGKDLLLKCLTFNPAKRISAYSALSHPYFQDLERCKENLDSHLPPSQNTSELNTA.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on CDK6 and/or interfere withor block the kinase activity of CDK6 or the ability of CDK6 tophosphorylate one or more CDK6 substrates. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human CDK6 (SEQ ID NO: 375) selected from the groupconsisting of Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181,Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200, or theequivalent amino acid residue(s) in a CDK6 protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of human CDK6 (SEQ ID NO: 375) selected from thegroup consisting of Asp-145, Val-180, and Tyr-196, or the equivalentamino acid residue(s) in a CDK6 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman CDK6 (SEQ ID NO: 375) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −975, −1000, −1025, −1050 kcal/mol, or greater. Therequisite binding affinity can correspond to a binding affinity that canbe detected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and histone methyl transferase (HMT), any HMT proteinsequence can be used. The HMT sequence used for modeling generally foldsinto a functional HMT protein or a functional fragment thereof. The HMTprotein sequence used for modeling can be selected based on the type ofsubject that the anti-inflammatory polypeptide is intended to treat(e.g., a human HMT is selected if the intended subject is a human, abovine HMT is selected if the intended subject is a cow, etc.). Thesequence used for modeling can be, for example, the Paramecium bursariaChlorella virus 1 HMT sequence (NCBI Acc. No. NP_048968.1), which is asfollows:

(SEQ ID NO: 376) MFNDRVIVKKSPLGGYGVFARKSFEKGELVEECLCIVRHNDDWGTALEDYLFSRKNMSAMALGFGAIFNHSKDPNARHELTAGLKRMRIFTIKPIAIGEE ITISYGDDYWLSRPRLTQN.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on HMT and/or interfere withor block the methyl transferase activity of HMT or the ability of HMT tomethylate histone substrates. For example, the anti-inflammatorypolypeptide can bind to at least one amino acid residue of Parameciumbursaria HMT (SEQ ID NO: 376) selected from the group consisting ofAsn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, and Asn-75, or theequivalent amino acid residue(s) in a HMT protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of Paramecium bursaria HMT (SEQ ID NO: 376)selected from the group consisting of Tyr-16, Glu-48, Tyr-50, Leu-51,Phe-52, and Asn-69, or the equivalent amino acid residue(s) in a HMTprotein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind toParamecium bursaria HMT (SEQ ID NO: 376) with an affinity of at least−600 kcal/mol, and in certain embodiments at least −650, −700, −750,−800, −850, −900, −925, −950, −975, −1000, −1025, −1050 kcal/mol, orgreater. The requisite binding affinity can correspond to a bindingaffinity that can be detected in vitro or in vivo. Alternatively, therequisite binding affinity can correspond to a binding affinity that canbe detected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and CD47, any CD47 protein sequence can be used. The CD47sequence used for modeling generally folds into a functional CD47protein or a SIRP-α-binding portion thereof. The CD47 protein sequenceused for modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human CD47is selected if the intended subject is a human, a bovine CD47 isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human CD47 sequence (NCBI Acc. No. XP_005247966.1),which is as follows:

(SEQ ID NO: 377) MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the SIRP-α-binding site on HMT and/orinterfere with or block the binding of CD47 to SIRP-α. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of CD47 (SEQ ID NO: 377) selected from the group consisting ofGlu-29. Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49, Asp-51, Glu-97,Thr-99, Leu-101, Thr-102, Arg-103, Glu-104, and Glu-106, or theequivalent amino acid residue(s) in a CD47 protein of another species.In certain embodiments, the anti-inflammatory polypeptide can bind to atleast one amino acid residue of CD47 (SEQ ID NO: 377) selected from thegroup consisting of Glu-29, Glu-35, Lys-39, Glu-97, Leu-101, Thr-102,Arg-103, Glu-104, and Glu-106, or the equivalent amino acid residue(s)in a CD47 protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human CD47 (SEQ ID NO: 377) selected from the groupconsisting of Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, and Asn-6 Tyr-37,Thr-49, Phe-50, Asp-51, Ala-53, Glu-97, Val-98, Glu-100, Leu-101,Thr-102, Glu-104, Glu-106, Gly-107, or the equivalent amino acidresidue(s) in a CD47 protein of another species. In certain embodiments,the anti-inflammatory polypeptide can bind to at least one amino acidresidue of CD47 (SEQ ID NO: 377) selected from the group consisting ofTyr-37, Glu-97, Glu-100, Leu-101, Glu-104, Glu-106, or the equivalentamino acid residue(s) in a CD47 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman CD47 (SEQ ID NO: 377) with an affinity of at least −550 kcal/mol,and in certain embodiments at least −600, −650, −675, −700, −725, −750,−775, −800 kcal/mol, or greater. The requisite binding affinity cancorrespond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and SIRP-α, any SIRP-α protein sequence can be used. TheSIRP-α sequence used for modeling generally folds into a functionalSIRP-α protein or a CD47-binding fragment thereof. The SIRP-α proteinsequence used for modeling can be selected based on the type of subjectthat the anti-inflammatory polypeptide is intended to treat (e.g., ahuman SIRP-α is selected if the intended subject is a human, a bovineSIRP-α is selected if the intended subject is a cow, etc.). The sequenceused for modeling can be the human SIRP-α sequence (GenBank Acc. No.AAH26692.1), which is as follows:

(SEQ ID NO: 378) MEPAGPAPGRLGPLLCLLLAASCAWSGVAGEEELQVITQPDKSVSVAAGESAILHCTVTSLIPVGPIQWFRGAGPARELIYNQKEGHFPRVTTVSESTKRENMDFSISISNITPADAGTYYCVKFRKGSPDTEFKSGAGTELSVRAKPSAPVVSGPAARATPQHTVSFTCESHGFSPRDITLKWFKNGNELSDFQTNVDPVGESVSYSIHSTAKVVLTREDVHSQVICEVAHVTLQGDPLRGTANLSETIRVPPTLEVTQQPVRAENQVNVTCQVRKFYPQRLQLTWLENGNVSRTETASTVTENKDGTYNWMSWLLVNVSAHRDDVKLTCQVEHDGQPAVSKSHDLKVSAHPKEQGSNTAAENTGSNERNIYIVVGVVCTLLVALLMAALYLVRIRQKKAQGSTSSTRLHEPEKNAREITQVQSLDTNDITYADLNLPKGKKPAPQAAEPNNHTEYASIQTSPQPASEDTLTYADLDMVHLNRTPKQPAPKPEPSFSEY ASVQVPRK.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the HMT-binding site on SIRP-α and/orinterfere with or block the binding of SIRP-α to HMT. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of SIRP-α (SEQ ID NO: 378) selected from the group consisting ofLeu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67, Arg-69, Met-72, Phe-74,Lys-96 and Asp-100, or the equivalent amino acid residue(s) in a SIRP-αprotein of another species. Alternatively, the anti-inflammatorypolypeptide can bind to at least one amino acid residue of human SIRP-α(SEQ ID NO: 378) selected from the group consisting of Tyr-50, Gln-52,Pro-58, Ser-66, Thr-67, and Ser-77, or the equivalent amino acidresidue(s) in a SIRP-α protein of another species. In certainembodiments, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of SIRP-α (SEQ ID NO: 378) selected from the groupconsisting of Tyr-50, Gln-52, Ser-66, and Thr-67, or the equivalentamino acid residue(s) in a SIRP-α protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman SIRP-α (SEQ ID NO: 378) with an affinity of at least −600kcal/mol, and in certain embodiments at least −650, −700, −750, −800,−825, −850, −875, −900, −925, −950, −975, −1000 kcal/mol, or greater.The requisite binding affinity can correspond to a binding affinity thatcan be detected in vitro or in vivo. Alternatively, the requisitebinding affinity can correspond to a binding affinity that can bedetected in silico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and CD206, any CD206 protein sequence can be used. TheCD206 sequence used for modeling generally folds into a functional CD206protein or a mannose-binding fragment thereof. The CD206 proteinsequence used for modeling can be selected based on the type of subjectthat the anti-inflammatory polypeptide is intended to treat (e.g., ahuman CD206 is selected if the intended subject is a human, a bovineCD206 is selected if the intended subject is a cow, etc.). The sequenceused for modeling can be the human CD206 sequence (NCBI Acc. No.NP_002429.1), which is as follows:

(SEQ ID NO: 379) MRLPLLLVFASVIPGAVLLLDTRQFLIYNEDHKRCVDAVSPSAVQTAACNQDAESQKFRWVSESQIMSVAFKLCLGVPSKTDWVAITLYACDSKSEFQKWECKNDTLLGIKGEDLFFNYGNRQEKNIMLYKGSGLWSRWKIYGTTDNLCSRGYEAMYTLLGNANGATCAFPFKFENKWYADCTSAGRSDGWLWCGTTTDYDTDKLFGYCPLKFEGSESLWNKDPLTSVSYQINSKSALTWHQARKSCQQQNAELLSITEIHEQTYLTGLTSSLTSGLWIGLNSLSFNSGWQWSDRSPFRYLNWLPGSPSAEPGKSCVSLNPGKNAKWENLECVQKLGYICKKGNTTLNSFVIPSESDVPTHCPSQWWPYAGHCYKIHRDEKKIQRDALTTCRKEGGDLTSIHTIEELDFIISQLGYEPNDELWIGLNDIKIQMYFEWSDGTPVTFTKWLRGEPSHENNRQEDCVVMKGKDGYWADRGCEWPLGYICKMKSRSQGPEIVEVEKGCRKGWKKHHFYCYMIGHTLSTFAEANQTCNNENAYLTTIEDRYEQAFLTSFVGLRPEKYFWTGLSDIQTKGTFQWTIEEEVRFTHWNSDMPGRKPGCVAMRTGIAGGLWDVLKCDEKAKFVCKHWAEGVTHPPKPTTTPEPKCPEDWGASSRTSLCFKLYAKGKHEKKTWFESRDFCRALGGDLASINNKEEQQTIWRLITASGSYHKLFWLGLTYGSPSEGFTWSDGSPVSYENWAYGEPNNYQNVEYCGELKGDPTMSWNDINCEHLNNWICQIQKGQTPKPEPTPAPQDNPPVTEDGWVIYKDYQYYFSKEKETMDNARAFCKRNFGDLVSIQSESEKKFLWKYVNRNDAQSAYFIGLLISLDKKFAWMDGSKVDYVSWATGEPNFANEDENCVTMYSNSGFWNDINCGYPNAFICQRHNSSINATTVMPTMPSVPSGCKEGWNFYSNKCFKTFGFMEEERKNWQEARKACIGFGGNLVSIQNEKEQAFLTYHMKDSTFSAWTGLNDVNSEHTFLWTDGRGVHYTNWGKGYPGGRRSSLSYEDADCVVIIGGASNEAGKWMDDTCDSKRGYICQTRSDPSLTNPPATIQTDGFVKYGKSSYSLMRQKFQWHEAETYCKLHNSLIASILDPYSNAFAWLQMETSNERVWIALNSNLTDNQYTWTDKWRVRYTNWAADEPKLKSACVYLDLDGYWKTAHCNESFYFLCKRSDEIPATEPPQLPGRCPESDHTAWIPFHGHCYYIESSYTRNWGQASLECLRMGSSLVSIESAAESSFLSYRVEPLKSKTNFWIGLFRNVEGTWLWINNSPVSFVNWNTGDPSGERNDCVALHASSGFWSNIHCSSYKGYICKRPKIIDAKPTHELLTTKADTRKMDPSKPSSNVAGVVIIVILLILTGAGLAAYFFYKKRRVHLPQEGAFENTLYFNSQSSPGTSDMKDLVGNIEQ NEHSVI.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the mannose-binding site on CD206 and/orinterfere with or block the binding of SIRP-mannose to CD206. Forexample, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of CD206 (SEQ ID NO: 379) selected from the groupconsisting of Glu-725, Tyr-729, Glu-733, Asn-747, and Asp-748, or theequivalent amino acid residue(s) in a CD206 protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of human CD206 (SEQ ID NO: 379) selected from thegroup consisting of Phe-708, Thr-709, Trp-710, Pro-714, Glu-719,Asn-720, Trp-721, Ala-722, Glu-725, Tyr-729, Glu-733, Asn-747, Asp-748,Ser-1691, Cys-1693, Phe-1694, and Phe-1703, or the equivalent amino acidresidue(s) in a CD206 protein of another species. In certainembodiments, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of CD206 (SEQ ID NO: 379) selected from the groupconsisting of Phe-708, Trp-710, Trp-721, Glu-725, Tyr-729, Glu-733, orthe equivalent amino acid residue(s) in a CD206 protein of anotherspecies.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman CD206 (SEQ ID NO: 379) with an affinity of at least −650 kcal/mol,and in certain embodiments at least −700, −750, −800, −850, −900, −925,−950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisitebinding affinity can correspond to a binding affinity that can bedetected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and TGM2, any TGM2 protein sequence can be used. The TGM2sequence used for modeling generally folds into a functional TGM2protein or acyl-transferase catalytic fragment thereof. The TGM2 proteinsequence used for modeling can be selected based on the type of subjectthat the anti-inflammatory polypeptide is intended to treat (e.g., ahuman TGM2 is selected if the intended subject is a human, a bovine TGM2is selected if the intended subject is a cow, etc.). The sequence usedfor modeling can be the human TGM2 sequence (GenBank Acc. No.AAB95430.1), which is as follows:

(SEQ ID NO: 380) MMDASKELQVLHIDFLNQDNAVSHHTWEFQTSSPVFRRGQVFHLRLVLNQPLQSYHQLKLEFSTGPNPSIAKHTLWLDPRTPSDHYNWQATLQNESGKEVTVAVTSSPNAILGKYQLNVKTGNHILKSEENILYLLFNPWCKEDMVFMPDEDERKEYILNDTGCHYVGAARSIKCKPWNFGQFEKNVLDCCISLLTESSLKPTDRRDPVLVCRAMCAMMSFEKGQGVLIGNWTGDYEGGTAPYKWTGSAPILQQYYNTKQAVCFGQCWVFAGILTTVLRALGIPARSVTGFDSAHDTERNLTVDTYVNENGEKITSMTHDSVWNFHVWTDAWMKRPDLPKGYDGWQAVDATPQERSQGVFCCGPSPLTAIRKGDIFIVYDTRFVFSEVNGDRLIWLVKMVNGQEELHVISMETTSIGKNISTKAVGQDRRRDITYEYKYPEGSSEERQVMDHAFLLLSSEREHRRPVKENFLHMSVQSDDVLLGNSVNFTVILKRKTAALQNVNILGSFELQLYTGKKMAKLCDLNKTSQIQGQVSEVTLTLDSKTYINSLAILDDEPVIRGFIIAEIVESKEIMASEVFTSFQYPEFSIELPNTGRIGQLLVCNCIFKNTLAIPLTDVKFSLESLGISSLQTSDHGTVQPGETIQSQIKCTPIKTGPKKFIVKLSSKQVKEINAQKIVLITK.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on TGM2 and/or interfere withor block the acyl-transferase activity of TGM2. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of TGM2 (SEQ ID NO: 380) selected from the group consisting ofCys-277, His-335, and Asp-358, or the equivalent amino acid residue(s)in a TGM2 protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman TGM2 (SEQ ID NO: 380) with an affinity of at least −650 kcal/mol,and in certain embodiments at least −700, −750, −800, −850, −900, −925,−950, −975, −1000, −1025, −1050 kcal/mol, or greater. The requisitebinding affinity can correspond to a binding affinity that can bedetected in vitro or in vivo. Alternatively, the requisite bindingaffinity can correspond to a binding affinity that can be detected insilico, e.g., using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and serum albumin, any serum albumin protein sequence canbe used. The serum albumin sequence used for modeling generally foldsinto a functional serum albumin protein or a functional fragmentthereof. The serum albumin protein sequence used for modeling can beselected based on the type of subject that the anti-inflammatorypolypeptide is intended to treat (e.g., a human serum albumin (HSA) isselected if the intended subject is a human, a bovine serum albumin(BSA) is selected if the intended subject is a cow, etc.). The sequenceused for modeling can be the human serum albumin (HSA) sequence (NCBIAcc. No. NP_000468.1), which is as follows:

(SEQ ID NO: 381) DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to HSA under physiological conditions (e.g., inthe blood stream).

In certain embodiments, an anti-inflammatory polypeptide can bind to HSA(SEQ ID NO: 381) with an affinity of at least −650 kcal/mol, and incertain embodiments at least −700, −750, −800, −850, −900, −925, −950,−975, −1000, −1025, −1050 kcal/mol, or greater. The requisite bindingaffinity can correspond to a binding affinity that can be detected invitro or in vivo. Alternatively, the requisite binding affinity cancorrespond to a binding affinity that can be detected in silico, e.g.,using the ClusPro™ algorithm.

In certain embodiments, an anti-inflammatory polypeptide binds to two ormore targets (e.g., pro-inflammatory targets). In some embodiments, ananti-inflammatory polypeptide binds to three, four, five, or morepro-inflammatory targets. For example, an anti-inflammatory polypeptidecan bind to any combination of targets disclosed herein. Such bindingcan be based on in silico, in vitro, or in vivo data. Thus, ananti-inflammatory polypeptide can bind to two or more NF-kB Class IIsubunits (e.g., RelB and at least one other NF-kB Class II subunit, suchas RelA, cRel, NF-kB1, or NF-kB2). Alternatively (or in addition), ananti-inflammatory polypeptide can bind to an NF-kB Class II subunit(e.g., RelB) and at least one other signaling molecule (e.g., at leastone signaling molecule selected from the group consisting of TGFβ,Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, CDK6, CD206, CD47, SIRP-α, HMT,and TGM2). For example, an anti-inflammatory polypeptide can bind to anNF-kB Class II subunit (e.g., RelB) and at least one signaling moleculeselected from the group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R,IL10R, EGFR, and CDK6. Alternatively, an anti-inflammatory polypeptidecan bind to an NF-kB Class II subunit (e.g., RelB) and at least onesignaling molecule selected from the group consisting of CD206, CD47,SIRP-α, and TGM2. In other alternatives, an anti-inflammatorypolypeptide can bind to an NF-kB Class II subunit (e.g., RelB) and HMT.In other alternatives, an anti-inflammatory polypeptide can bind to atleast one signaling molecule selected from the group consisting of TGFβ,Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6, and at least onesignaling molecule selected from the group consisting of CD206, CD47,SIRP-α, and TGM2. In other alternatives, an anti-inflammatorypolypeptide can bind to at least one signaling molecule selected fromthe group consisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR,and CDK6, and also bind to HMT. In still other embodiments, ananti-inflammatory polypeptide can bind to an NF-kB Class II subunit(e.g., RelB), at least one signaling molecule selected from the groupconsisting of TGFβ, Notch1, Wnt8R, TRAIL, IL6R, IL10R, EGFR, and CDK6,at least one signaling molecule selected from the group consisting ofCD206, CD47, SIRP-α, and TGM2, and also HMT. In certain embodiments, ananti-inflammatory polypeptide binds to two or more pro-inflammatorytargets and also serum albumin (e.g., human serum albumin).

For modeling interactions between potential anti-inflammatorypolypeptides and LEGUMAIN, any LEGUMAIN protein sequence can be used.The LEGUMAIN sequence used for modeling generally folds into afunctional LEGUMAIN protein or a functional fragment thereof. TheLEGUMAIN protein sequence used for modeling can be selected based on thetype of subject that the anti-inflammatory polypeptide is intended totreat (e.g., a human LEGUMAIN is selected if the intended subject is ahuman, a bovine LEGUMAIN is selected if the intended subject is a cow,etc.). The sequence used for modeling can be the human LEGUMAIN sequence(GenBank Acc. No. AAH03061.1).

(SEQ ID NO: 137)

IVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVTPQNFLAVLRGDAEAVKGIGSG

HTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVTHLDLTPSPDVPLTIMKRKLMNTNDLEESRQLTEEIQRHLDARHLIEKSVRKIVSLLAASEAEVEQLLSERAPLTGHSCYPEALLHFRTHCFNWHSPTYEYALRHLYVLVNLCEKPYPLHRIKLSMDHVCLGHY.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on LEGUMAIN and/or interferewith or block the ability of LEGUMAIN to bind to its target. Forexample, the anti-inflammatory polypeptide can bind to at least oneamino acid residue of human LEGUMAIN (SEQ ID NO: 137) selected from thegroup consisting of Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217,Ser-218 and Asp-233, or the equivalent amino acid residue(s) in aLEGUMAIN protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human LEGUMAIN (SEQ ID NO: 137) selected from the groupconsisting of Asn-44, Glu-189 and Asp-233, or the equivalent amino acidresidue(s) in a LEGUMAIN protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman LEGUMAIN (SEQ ID NO: 137) with an affinity of at least −600kcal/mol, and in certain embodiments at least −650, −700, −750, −800,−850, −900, −925, −950 kcal/mol, or greater. The requisite bindingaffinity can correspond to a binding affinity that can be detected invitro or in vivo. Alternatively, the requisite binding affinity cancorrespond to a binding affinity that can be detected in silico, e.g.,using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and CD209, any CD209 protein sequence can be used. TheCD209 sequence used for modeling generally folds into a functional CD209protein or a functional fragment thereof. The CD209 protein sequenceused for modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human CD209is selected if the intended subject is a human, a bovine CD209 isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human CD209 sequence (GenBank Acc. No.NP_001138366.1).

(SEQ ID NO: 140)MSDSKEPRLQQLGLLVSKVPSSISQEQSRQDAIYQKLTQLKAAVGELSEKSKLQEIYQELTQLKAAVGELPEKSKLQEIYQELTRLKAAVGELPEKSKLQEIYQELTWLKAAVGELPEKSKMQEIYQELTRLKAAVGELPEKSKQQEIYQELTRLKAAVGELPEKSKQQEIYQELTRLKAAVGELPEKSKQQEIYQELTQLKAAVERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQ

NLAKFWICKKSAASCSRDEEQFLSPAPATPNPPPA

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on CD209 and/or interfere withor block the ability of CD209 to bind to its receptor. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human CD209 (SEQ ID NO: 140) selected from the groupconsisting of Phe-269, Glu-280, Glu-303, Asn-305, Asn-306, Glu-310,Asp-311, Ser-316, Gly-317, Asn-321 and Lys-324 or the equivalent aminoacid residue(s) in a CD209 protein of another species. Alternatively,the anti-inflammatory polypeptide can bind to at least one amino acidresidue of human CD209 (SEQ ID NO: 140) selected from the groupconsisting of Phe-269, Glu-280, Glu-303, Glu-310, Asp-311, Asn-321 andLys-324, or the equivalent amino acid residue(s) in a CD209 protein ofanother species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman CD209 (SEQ ID NO: 140) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −1,000, −1,050 kcal/mol, or greater. The requisite bindingaffinity can correspond to a binding affinity that can be detected invitro or in vivo. Alternatively, the requisite binding affinity cancorrespond to a binding affinity that can be detected in silico, e.g.,using the ClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and FAS, any FAS protein sequence can be used. The FASsequence used for modeling generally folds into a functional FAS proteinor a functional fragment thereof. The FAS protein sequence used formodeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human FAS isselected if the intended subject is a human, a bovine FAS is selected ifthe intended subject is a cow, etc.). The sequence used for modeling canbe the human FAS sequence (NCBI Reference Sequence: NP_000034.1).

(SEQ ID NO: 152)MLGIWTLLPLVLTSVARLSSKSVNAQVTDINSKGLELRKTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKEEGSRSNLGWLCLLLLPIPLIVWVKRKEV

NFRNEIQSLV.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on FAS and/or interfere withor block the ability of FAS to bind to its ligand. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human FAS (SEQ ID NO: 152) selected from the group consistingof Lys-251, Lys-296, Lys-299. Leu-303, Leu-306, Ala-307, Glu-308,Lys-309, Gln-311. Ile-314, Leu-315, Asp-317, Ile-318 and Thr-319, or theequivalent amino acid residue(s) in a FAS protein of another species.Alternatively, the anti-inflammatory polypeptide can bind to at leastone amino acid residue of human FAS (SEQ ID NO: 152) selected from thegroup consisting of Lys-296, Lys-299, Leu-306, Ala-307, Glu-308,Ile-314, Leu-315, Asp-317 and Ile-318, or the equivalent amino acidresidue(s) in a FAS protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman FAS (SEQ ID NO: 152) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950 kcal/mol, or greater. The requisite binding affinity cancorrespond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

Programmed cell death protein 1, also known as PD-1 and CD279 (clusterof differentiation 279), is a protein that in humans is encoded by thePDCD1 gene. PD-1 is a cell surface receptor that belongs to theimmunoglobulin superfamily and is expressed on T cells and pro-B cells.PD-1 binds two ligands, PD-L1 and PD-L2, PD-1, functioning as an immunecheckpoint plays an important role in down regulating the immune systemby preventing the activation of T-cells, which in turn reducesautoimmunity and promotes self-tolerance. The inhibitory effect of PD-1is accomplished through a dual mechanism of promoting apoptosis(programmed cell death) in antigen specific T-cells in lymph nodes whilesimultaneously reducing apoptosis in regulatory T cells (suppressor Tcells).

For modeling interactions between potential anti-inflammatorypolypeptides and PD-1, any PD-1 protein sequence can be used. The PD-1sequence used for modeling generally folds into a functional PD-1protein or a functional fragment thereof. The PD-1 protein sequence usedfor modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human PD-1is selected if the intended subject is a human, a bovine PD-1 isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human PD-1 sequence (Locus: XP_006712636.1).

(SEQ ID NO: 159)

KAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRA ARG.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on PD-1 and/or interfere withor block the ability of PD-1 to bind to its receptor. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human PD-1 (SEQ ID NO: 159) selected from the groupconsisting of Val-64. Asn-66, Tyr-68, Met-70, Thr-76, Lys-78, Thr-120,Leu-122, Ala-125, Ser-127, or the equivalent amino acid residue(s) in aPD-1 protein of another species. Alternatively, the anti-inflammatorypolypeptide can bind to at least one amino acid residue of human PD-1(SEQ ID NO: 159) selected from the group consisting of Tyr-68, Met-70,Lys-78 and Leu-122, or the equivalent amino acid residue(s) in a PD-1protein of another species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman PD-1 (SEQ ID NO: 159) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −1,000 kcal/mol, or greater. The requisite binding affinitycan correspond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

Dual specificity mitogen-activated protein kinase kinase 7, also knownas MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encodedby the MAP2K7 gene. This protein is a member of the mitogen-activatedprotein kinase kinase family. The MKK7 protein exists as six differentisoforms with three possible N-termini (α, β, and γ isoforms) and twopossible C-termini (1 and 2 isoforms). MKK7 is involved in signaltransduction mediating the cell responses to proinflammatory cytokines,and environmental stresses. This kinase specifically activatesMAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated andactivated by MAP kinase kinase kinases including MAP3K1/MEKK1,MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.

For modeling interactions between potential anti-inflammatorypolypeptides and MKK7, any MKK7 protein sequence can be used. The MKK7sequence used for modeling generally folds into a functional MKK7protein or a functional fragment thereof. The MKK7 protein sequence usedfor modeling can be selected based on the type of subject that theanti-inflammatory polypeptide is intended to treat (e.g., a human MKK7is selected if the intended subject is a human, a bovine MKK7 isselected if the intended subject is a cow, etc.). The sequence used formodeling can be the human MKK7 sequence (NCBI Reference Sequence:NP_001284484.1).

(SEQ ID NO: 166)MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPIIVITTSPAPAPSQRAALQLPLANDGGSRSPSSESSPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQ

ISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDCLTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on MKK7 and/or interfere withor block the ability of MKK7 to bind to its receptor. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human MKK7 (SEQ ID NO: 166) selected from the groupconsisting of Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215,Thr-217, Lys-221, Leu-266, Cys-276 and Asp-277, or the equivalent aminoacid residue(s) in a MKK7 protein of another species. Alternatively, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human MKK7 (SEQ ID NO: 166) selected from the groupconsisting of Met-142, Val-150, Lys-165, Met-212, Met-215, Leu-266 andAsp-277, or the equivalent amino acid residue(s) in a MKK7 protein ofanother species.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman MKK7 (SEQ ID NO: 166) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −1,000 kcal/mol, or greater. The requisite binding affinitycan correspond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

For modeling interactions between potential anti-inflammatorypolypeptides and ribonucleotide reductase (RNR), any RNR proteinsequence can be used. The RNR sequence used for modeling generally foldsinto a functional RNR protein or a functional fragment thereof. The RNRprotein sequence used for modeling can be selected based on the type ofsubject that the anti-inflammatory polypeptide is intended to treat(e.g., a human RNR is selected if the intended subject is a human, abovine RNR is selected if the intended subject is a cow, etc.). Thesequence used for modeling can be the yeast RNR sequence (GenBank:AJV34160.1).

(SEQ ID NO: 168)MYVYKRDGRKEPVQFDKITARISRLCYGLDPKHIDAVKVTQRIISGVYEGVTTIELDNLAAETCAYMTTVHPDYATLAARIAISNLHKQTTKQFSKVVEDLYRYVNAATGKPAPMISDDVYNIVMENKDKLNSAIVYDRDFQYSYFGFKTLERSYLLRINGQVAERPQHLIMRVALGIHGRDIEAALETYNLMSLKYYTHASPTLFNAGTPKPQMSSCFLVAMKEDSIEGIYDTLKECALISKTAGGIGLHIHNIRSTGSYIAGTNGTSNGLIPMIRVFNNTARYVDQGGNKRPGAFALYLEPWHADIFDFIDIRKNHGKEEIRARDLFPALWTPDLFMKRVEENGTWTLFSPTSAPGLSDCYGDEFEALYTRYEKEGRGKTIKAQKLWY

TSEDGKTSTYNFKKLHEIAKVVTRNLNRVIDRNYYPVEEARKSNMRHRPIALGVQGLADTFMLLRLPFDSEEARLLNIQIFETIYHASMEASCELAQKDGPYETFQGSPASQGILQFDMWDQKPYGMWDW

DLGIWDEGMKQYLITQNGSIQGLPNVPQELKDLYKTVWEISQKTIINMAADRSVYIDQSHSLNLFLRAPTMGKLTSMHFYGWKKGLKTGMYYLRTQAASAAIQFTIDQKIADQATENVADISNLKRPSYMPSSASYAASDFVPAAVTANATIPSLDSSSEASREASPAPTGSHSLTKGMAELNVQESKVEVPEVPAPTKNEEKAAPIVDDEETEFDIYNSKVIACAIDNPEACEMCSG.

An anti-inflammatory polypeptide can be identified, for example, basedon its ability to bind to the active site on RNR and/or interfere withor block the ability of RNR to bind to its receptor. For example, theanti-inflammatory polypeptide can bind to at least one amino acidresidue of human RNR (SEQ ID NO: 168) selected from the group consistingof Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608 and Ala-610, orthe equivalent amino acid residue(s) in a RNR protein of anotherspecies.

In certain embodiments, an anti-inflammatory polypeptide can bind tohuman RNR (SEQ ID NO: 168) with an affinity of at least −600 kcal/mol,and in certain embodiments at least −650, −700, −750, −800, −850, −900,−925, −950, −1,000 kcal/mol, or greater. The requisite binding affinitycan correspond to a binding affinity that can be detected in vitro or invivo. Alternatively, the requisite binding affinity can correspond to abinding affinity that can be detected in silico, e.g., using theClusPro™ algorithm.

Excluded Polypeptides

Compositions of the invention optionally exclude polypeptides thatsatisfy the Structural Algorithm described herein which may have beenknown in the art prior to the filing of the present application. Variouspublications have discussed synthetic and naturally occurringanti-inflammatory polypeptides and/or polypeptides having a striapathicsequence including, for example, US Patent Application Nos. 201210270770and 2003/0109452, and U.S. Pat. No. 6,559,281. Accordingly, one or morepolypeptides and/or uses of such polypeptides described in suchpublications can be excluded from the scope of the presently disclosedcomposition and/or methods. For example, peptide RP-398 (SEQ ID NO: 155)is optionally excluded from compositions disclosed herein and/or methodsof using such compositions. Moreover, any of the polypeptides disclosedin Tables 3-9, below, can be optionally excluded from compositionsdisclosed herein and/or methods of using such compounds.

Linked Anti-Inflammatory Polypeptide Combinations

The invention further includes any two anti-inflammatory polypeptideswhich have been linked together. The linkage can be formed by a peptidelinker, such as a Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR; SEQ ID NO:412), Gly-Pro-Gly (GPG), or Gly-Pro-Gly-Arg (GPGR; SEQ ID NO: 413)sequence, that links the C-terminal end of a first anti-inflammatorypolypeptide to the N-terminal end of a second anti-inflammatorypolypeptide. Alternatively, the linkage can be a peptoid linker (e.g., apoly N-substituted version of any of the foregoing peptide linkers), apolymer containing g-amino acids (e.g., corresponding to any of theforegoing peptide linkers), or a non-peptide, chemical linker. Thelinked anti-inflammatory polypeptides can be any of the polypeptidesdisclosed herein (e.g., in Tables 3-9), and can include the samepolypeptide being linked to form a homodimer or different polypeptidesbeing linked to form a heterodimer. Techniques for linking peptides viapeptide and non-peptide linkers are well known in the art, and theinventive polypeptide combinations are intended to encompass all suchlinkages.

Anti-inflammatory polypeptides can be linked to another molecule via abiodegradable linkage, such as a disulfide bond. The disulfide bond canbe mediated by the sulfhydryl group of a cysteine residue found in theanti-inflammatory polypeptide and a sulfhydryl group in the othermolecule. The cysteine residue can be, e.g., located at either theC-terminal or N-terminal end of anti-inflammatory polypeptide. Specificexamples include RP-433 (FAKKFAKKFKC, SEQ ID NO: 384) and RP-434(KFRKAFKRFFC; SEQ ID NO: 385), though any of the peptides disclosedherein could be similarly modified. Using a disulfide linkage of thissort, polypeptides of the invention can be conveniently linked tovarious types of useful molecules. For example, the linkage can be withanother anti-inflammatory polypeptide (which optionally includes aC-terminal or N-terminal cysteine residue), a fluorescent label (e.g.,Dylight 350), a chemotherapeutic agent (e.g., a taxol derivative formedby adding a sulfhydral group to an appropriate site on the taxol ringstructure, followed by oxidation with a cysteine-containing peptide ofthe invention), or the like.

Linked anti-inflammatory polypeptides (e.g., homo- or heterodimers) canbind to a target molecule (e.g., a target protein, such as apro-inflammatory signaling protein) with a binding energy that isgreater than that of either monomer polypeptide alone. Thus, forexample, the energy of binding of linked anti-inflammatory polypeptidesto an NF-kB Class II protein (e.g., RelB) can be at least −700 kcal/mol,and in certain embodiments at least −750, −800, −900, −1000, −1100,−1200, −1250, −1300, −1350, −1400, −1425, −1450, −1475, −1500, −1525,−1550, −1575, −1600 kcal/mol, or greater. The energy of binding can bedetermined, e.g., in silico, in vitro, or in vivo, using methodswell-known in the art (e.g., using the ClusPro™ algorithm).

Modified Polypeptides

Embodiments of the invention include the modification of any of theanti-inflammatory polypeptides of the invention, by chemical or geneticmeans. Examples of such modification include construction of peptides ofpartial or complete sequence with non-natural amino acids and/or naturalamino acids in L or D forms. For example, any of the peptides disclosedherein and any variants thereof could be produced in an all-D form.Furthermore, polypeptides of the invention can be modified to containcarbohydrate or lipid moieties, such as sugars or fatty acids,covalently linked to the side chains or the N- or C-termini of the aminoacids. In addition, the polypeptides of the invention can be modified toenhance solubility and/or half-life upon being administered. Forexample, polyethylene glycol (PEG) and related polymers have been usedto enhance solubility and the half-life of protein therapeutics in theblood. Accordingly, the polypeptides of the invention can be modified byPEG polymers and the like. Polypeptides of the invention can also bemodified to contain sulfur, phosphorous, halogens, metals, etc. Andamino acid mimics can be used to produce polypeptides of the invention(e.g., having a structure based on the Structural Algorithm or astructure similar to any of the anti-inflammatory polypeptides disclosedherein). In certain embodiments, polypeptides of the invention thatinclude amino acid mimics have enhanced properties, such as resistanceto degradation. For example, polypeptides of the invention can includeone or more (e.g., all) peptoid monomers.

Compositions

Compositions of the invention include an anti-inflammatory polypeptidethat satisfies the structural algorithm described herein. For example,the anti-inflammatory polypeptide can have a striapathic region having asequence that conforms with any one of Formulas I-LIV. In particular,the anti-inflammatory polypeptide can be any of the polypeptides listedin Table 3-9, or a fragment or variant thereof. Typically, theanti-inflammatory polypeptide included in the compositions of theinvention will be a synthetic polypeptide (e.g., made by chemicalsynthesis and/or produced recombinantly).

The compositions of the invention can include a single anti-inflammatorypolypeptide, or combinations thereof. The compositions can besubstantially free of proteins and other polypeptides that do notsatisfy the structural algorithm disclosed herein. As used herein, theterm “substantially free of proteins and other polypeptides” means thatless than 5% of the protein content of the composition is made up ofproteins and other polypeptides that are not an anti-inflammatorypolypeptide of the invention. A composition that is substantially freeof non-anti-inflammatory polypeptides of the invention can have lessthan 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or less of proteins orother polypeptides that do not satisfy the structural algorithmdisclosed herein. Thus, the compositions can be substantially free ofblood proteins, such as serum albumin, globulins, fibrinogen, andclotting factors. Alternatively, the compositions can be substantiallyfree of globulins, fibrinogen, and clotting factors, but can includepurified or recombinantly produced serum albumin.

The compositions of the invention in certain embodiments contain ananti-inflammatory polypeptide that is not naturally found in a human orother mammal or animal. However, compositions of the invention caninclude an anti-inflammatory polypeptide that is naturally found in ahuman or other mammal or animal, provided that the composition issubstantially free of biological molecules (such asnon-anti-inflammatory polypeptides, nucleic acids, lipids,carbohydrates, and metabolites) that are associated with theanti-inflammatory polypeptide in vivo or co-purify with theanti-inflammatory polypeptide. As used herein, the term “substantiallyfree of biological molecules” means that less than 5% of the dry weightof the composition is made up of biological molecules that are notanti-inflammatory polypeptides. A composition that is substantially freeof such biological molecules can have less than 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, 0.01%, or less of biological molecules that are notanti-inflammatory polypeptides. Thus, for example, the composition canbe substantially free of biological molecules that are abundant in theblood, such the proteins discussed above, fatty acids, cholesterol,non-protein clotting factors, metabolites, and the like. In addition,the composition can be substantially free of cells, including red bloodcells, white blood cells, and platelets, and cell fragments.

The compositions of the invention can include at least 1 mg (e.g., atleast 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600,700, 800, 900, 1000 mg, or more) of anti-inflammatory polypeptide. Thus,for example, the compositions can include an amount of anti-inflammatorypolypeptide equal to about 1 mg to about 1000 mg (e.g., about 5 mg toabout 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg,about 5 mg to about 600 mg, about 10 mg to about 500 mg, about 10 mg toabout 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg,about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg toabout 100 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg,about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg toabout 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg,about 75 mg to about 500 mg, about 75 mg to about 400 mg, about 75 mg toabout 300 mg, about 75 mg to about 250 mg, about 75 mg to about 200 mg,about 75 mg to about 150 mg, about 75 mg to about 100 mg, about 100 mgto about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, or anyother range containing two of the foregoing endpoints).

The compositions of the invention can include a solution that containsat least 1 mg/ml (e.g., at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/ml or more) of ananti-inflammatory polypeptide. Thus, for example, the compositions caninclude a solution having an anti-inflammatory polypeptide concentrationof about 1 mg/ml to about 1000 mg/ml (e.g., about 5 mg/ml to about 900mg/ml, about 5 mg/ml to about 800 mg/ml, about 5 mg/ml to about 700mg/ml, about 5 mg/ml to about 600 mg/ml, about 5 mg/ml to about 500mg/ml, about 10 mg/ml to about 500 mg/ml, about 10 mg/ml to about 400mg/ml, about 10 mg/ml to about 300 mg/ml, about 10 mg/ml to about 250mg/ml, about 10 mg/ml to about 200 mg/ml, about 10 mg/ml to about 150mg/ml, about 10 mg/ml to about 100 mg/ml, about 50 mg/ml to about 500mg/ml, about 50 mg/ml to about 400 mg/ml, about 50 mg/ml to about 300mg/ml, about 50 mg/ml to about 250 mg/ml, about 50 mg/ml to about 200mg/ml, about 50 mg/ml to about 150 mg/ml, about 50 mg/ml to about 100mg/ml, about 75 mg/ml to about 500 mg/ml, about 75 mg/ml to about 400mg/ml, about 75 mg/ml to about 300 mg/ml, about 75 mg/ml to about 250mg/ml, about 75 mg/ml to about 200 mg/ml, about 75 mg/ml to about 150mg/ml, about 75 mg/ml to about 100 mg/ml, about 100 mg/ml to about 500mg/ml, about 100 mg/ml to about 400 mg/ml, about 100 mg/ml to about 300mg/ml, about 100 mg/ml to about 250 mg/ml, about 100 mg/ml to about 200mg/ml, about 10 mg/ml to about 150 mg/ml, or any other range containingtwo of the foregoing endpoints).

The compositions of the invention include pharmaceutical compositions.Such pharmaceutical compositions can comprise one or moreanti-inflammatory polypeptides and a pharmaceutically acceptablecarrier. Pharmaceutical compositions can further include a protein otherthan an anti-inflammatory polypeptide of the invention and/or achemotherapeutic agent. The other protein can be a therapeutic agent,such as a therapeutic antibody. The therapeutic protein or antibody canhave anti-inflammatory properties or other properties that theanti-inflammatory polypeptides of the invention augment or are augmentedby. Alternatively, the other protein can be a carrier protein, such asserum albumin (e.g., HSA). The serum albumin (e.g., HAS, BSA, etc.) canbe purified or recombinantly produced. By mixing the anti-inflammatorypolypeptide(s) in the pharmaceutical composition with serum album, theanti-inflammatory polypeptides can be effectively “loaded” onto theserum albumin, allowing a greater amount of anti-inflammatorypolypeptide to be successfully delivered to a site of inflammation. Thechemotherapeutic agent can be, for example, an anti-cancerchemotherapeutic agent. Such chemotherapeutic agents include, but arenot limited to, Gemcitabine, Docetaxel. Bleomycin, Erlotinib, Gefitinib,Lapatinib, Imatinib, Dasatinib, Nilotinib, Bosutinib, Crizotinib,Ceritinib, Trametinib, Bevacizumab, Sunitinib, Sorafenib, Trastuzumab,Ado-trastuzumab emtansine, Rituximab, Ipilimumab, Rapamycin,Temsirolimus, Everolimus, Methotrexate, Doxorubicin, Abraxane,Folfirinox, Cisplatin, Carboplatin, 5-fluorouracil, Teysumo, Paclitaxel,Prednisone, Levothyroxine, and Pemetrexed.

Methods

The anti-inflammatory polypeptides of the invention provide powerfultools for reducing inflammation and/or treating conditions associatedwith excessive inflammation (whether acute or chronic). As used herein,the terms “treat.” “treating.” and similar words shall mean stabilizing,reducing the symptoms of, preventing the occurrence of, or curing amedical condition.

Accordingly, the invention provides methods of reducing the expressionlevel and/or activity of at least one (e.g., 2, 3, 4, 5, or more)pro-inflammatory cytokine(s) at a site of inflammation in a subject. Themethods include administering an anti-inflammatory polypeptide of theinvention (or, for example, a pharmaceutical composition comprising ananti-inflammatory polypeptide) to the subject. The pro-inflammatorycytokine can be selected from the group consisting of NF-kB, TNFα, IL-1,IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, and MMP-9. The reductioncan be a reduction of at least 10% (e.g., 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, or more) in the expression or activity of the cytokine.

The invention also provides methods of inhibiting an increase in theexpression level and/or activity of at least one (e.g., 2, 3, 4, 5, ormore) pro-inflammatory cytokine(s) at a potential site of inflammationin a subject. The methods include administering an anti-inflammatorypolypeptide of the invention (or, for example, a pharmaceuticalcomposition comprising an anti-inflammatory polypeptide) to the subject.The pro-inflammatory cytokine can be selected from the group consistingof NF-kB, TNFα, IL-1, IL-6, IL-8, IL-12, IL-17, IL-23, MCP-1, MMP-1, andMMP-9. The methods can inhibit increased cytokine expression and/oractivity by limiting such increases to no more than 20% (e.g., 15%,12.5%, 10%, 7.5%, 5%, 4%, 3%, 2%, 1%, or less).

The invention also provides a method of treating or preventing acondition associated with chronic inflammation. The condition associatedwith chronic inflammation can be irritable bowel disease, ulcerativecolitis, colitis. Crohn's disease, idiopathic pulmonary fibrosis,asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis,auto-immune diseases, a feline or human immunodeficiency virus (FIV orHIV) infection, cancer, age-related inflammation and/or stem celldysfunction (e.g., age-related increases in Nlrp3 expression,age-related elevation of SOCS3 in muscle stem cells, etc.),graft-versus-host disease (GVHD), keloids, scleroderma, obesity,diabetes, diabetic wounds, other chronic wounds, atherosclerosis,multiple sclerosis, Parkinson's disease. Alzheimer's disease, maculardegeneration, gout, gastric ulcers, gastritis, mucositis, toxoplasmosis,and chronic viral or microbial infections (e.g., such as chronicbacterial or protozoan infections). The methods includes administeringan anti-inflammatory polypeptide of the invention (or, for example, apharmaceutical composition comprising an anti-inflammatory polypeptide)to a subject suffering from or likely to develop the condition.

The invention also provides methods of treating or preventing fibrosis.The fibrosis can be, for example, pulmonary fibrosis, dermal fibrosis,hepatic fibrosis, renal fibrosis, or fibrosis caused by ionizingradiation. The methods include administering an anti-inflammatorypolypeptide of the invention (or, for example, a pharmaceuticalcomposition comprising an anti-inflammatory polypeptide) to a subjectsuffering from or likely to develop fibrosis.

The invention also provides methods of treating cancer. The cancer canbe colon cancer, breast cancer, leukemia, lymphoma, ovarian cancer,prostate cancer, liver cancer, lung cancer, testicular cancer, cervicalcancer, bladder cancer, endometrial cancer, kidney cancer, melanoma,cancers of the thyroid or brain, or ophthalmic cancer. The methodsinclude administering an anti-inflammatory polypeptide of the invention(or, for example, a pharmaceutical composition comprising ananti-inflammatory polypeptide) to a subject suffering from cancer.

For any of the foregoing methods, the subject can be an animal, such asa domesticated animal (e.g., a horse, cow, pig, goat, sheep, rabbit,chicken, turkey, duck, etc.), a pet (e.g., a dog, cat, rabbit, hamster,gerbil, bird, fish, etc.), a lab animal (e.g., a mouse, rat, monkey,chimpanzee, owl, fish, etc.), a zoo animal (e.g., a gorilla, orangutan,chimpanzee, monkey, elephant, camel, zebra, boar, lion, tiger, giraffe,bear, bird, etc.), a wild animal (e.g., a deer, wolf, mountain lion,bird, etc.), or a human.

In conjunction with any of the foregoing methods, the anti-inflammatorypolypeptide(s) can be administered at a dose and frequency that dependson the type of animal, the size of the animal, and the condition beingtreated. Typically, the anti-inflammatory polypeptide is administereddaily (or every other day, or weekly), in an amount between about 1 mgand about 1000 mg (e.g., about 5 mg to about 900 mg, about 5 mg to about800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 10mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about10 mg to about 150 mg, about 10 mg to about 100 mg, about 50 mg to about500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about150 mg, about 50 mg to about 100 mg, about 75 mg to about 500 mg, about75 mg to about 400 mg, about 75 mg to about 300 mg, about 75 mg to about250 mg, about 75 mg to about 200 mg, about 75 mg to about 150 mg, about75 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg toabout 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250mg, about 100 mg to about 200 mg, or any other range containing two ofthe foregoing endpoints). The daily dose can be administered once duringthe day, or broken up into smaller doses that are taken at multiple timepoints during the day. For a human (and other similarly-sized mammals),a dose of 5 mg/kg every other day can be administered. Theanti-inflammatory polypeptide can be administered for a fixed period oftime (e.g., for 2-3 weeks), at intervals (e.g., administer polypeptidefor 2-3 weeks, wait 2-3 weeks, then repeat the cycle), or until suchtime as the pro-inflammatory cytokine levels have been reduced orstabilized, the chronic inflammatory condition or fibrosis hasameliorated, or the cancer has gone into remission.

The administration of the anti-inflammatory polypeptides (orpharmaceutical compositions comprising such polypeptides) in conjunctionwith any of the foregoing methods can be performed intravenously,intraperitoneally, parenteral, orthotopically, subcutaneously,topically, nasally, orally, sublingually, intraocularly, by means of animplantable depot, using nanoparticle-based delivery systems,microneedle patch, microspheres, beads, osmotic or mechanical pumps,and/or other mechanical means.

In conjunction with any of the foregoing methods, the anti-inflammatorypolypeptides (or pharmaceutical compositions comprising suchpolypeptides) can be administered in combination with another drugdesigned to reduce or prevent inflammation, treat or prevent chronicinflammation or fibrosis, or treat cancer. In each case, theanti-inflammatory polypeptide can be administered prior to, at the sametime as, or after the administration of the other drug. For thetreatment of cancer, the anti-inflammatory polypeptide(s) can beadministered in combination with a chemotherapeutic agent selected fromthe group consisting of steroids, anthracyclines, thyroid hormonereplacement drugs, thymidylate-targeted drugs, Chimeric AntigenReceptor/T cell therapies, and other cell therapies. Specificchemotherapeutic agents include, for example, Gemcitabine, Docetaxel,Bleomycin, Erlotinib, Gefitinib, Lapatinib, Imatinib, Dasatinib,Nilotinib, Bosutinib, Crizotinib. Ceritinib, Trametinib, Bevacizumab,Sunitinib, Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab,Ipilimumab, Rapamycin, Temsirolimus, Everolimus, Methotrexate,Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin,5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, andPemetrexed.

Alternatively, for the methods of treating cancer, the anti-inflammatorypolypeptide(s) (or pharmaceutical compositions comprising suchpolypeptides) can be administered in combination with radiation therapy.Again, the anti-inflammatory polypeptide(s) can be administered priorto, or after the administration of the radiation therapy.

Any of the foregoing methods of the invention further include a step ofassessing the efficacy of the therapeutic treatment. Because theanti-inflammatory polypeptides of the invention have a demonstrableability to reduce tissue inflammation and suppress the excessiveproduction of inflammatory mediators such as IL-1, IL-6, IL-12, andTNFα, both in tissues and in serum (data not shown), the efficacy of thetherapeutic treatment can be assessed by measuring the levels of suchcytokines (e.g., in the serum) to determine whether the levels haveresponded appropriately to the treatment. Depending on the cytokinelevels, the dosage of anti-inflammatory polypeptide(s) can be adjustedup or down, as needed.

EXAMPLES Example 1 Peptide Designs

Polypeptides were designed in silico to include a striapathic region ofalternating X_(m) and Y_(n) modules, with each X_(m) module having oneto five hydrophilic amino acid residues and each Y_(n) module having oneto five hydrophobic residues.

Initial designs focused on polypeptides consisting of a striapathicregion having a total length of around 10 amino acid residues, with eachX_(m) module having one or two hydrophilic amino acid residues and eachY_(n) module having one or two hydrophobic residues, and with the ratioof hydrophobic to hydrophilic amino acid residues being around 1:1. Suchpolypeptides were predicted to have an amphipathic, helical secondarystructure, with a hydrophobic surface on one side of the helix and ahydrophilic surface on the opposite side of the helix.

Additional peptide designs were subsequently generated that maintained atotal length of around 10 amino acid residues, but expanded the numberof possible amino acid residues in a hydrophilic or hydrophobic modulefrom two to three and varied the hydrophobic to hydrophilic ratio. Forexample, larger hydrophobic modules having three hydrophobic amino acidresidues were coupled with shorter hydrophilic modules having onehydrophilic amino acid residue, giving rise to polypeptides predicted tohave a stronger hydrophobic character. Such peptides were predicted tomaintain an amphipathic, helical secondary structure, but have a largerhydrophobic surface on one side of the helix and a correspondinglysmaller hydrophilic surface on the other side. Similarly, largerhydrophilic modules having three hydrophilic amino acid residues werecoupled with shorter hydrophobic modules having one hydrophobic aminoacid residue, giving rise to peptides having a stronger hydrophiliccharacter. Such peptides were also predicted to maintain an amphipathic,helical secondary structure, but have a larger hydrophilic surface onone side of the helix and a correspondingly smaller hydrophobic surfaceon the other side.

Other peptide designs included: polypeptides having modules of four orfive hydrophilic amino acid residues and/or four or five hydrophobic;polypeptides having a total length of around 10 amino acid residues butlacking hydrophobic amino acid residues; polypeptides having hydrophilicand hydrophobic modules each consisting of a single amino acid residue;and proline-rich polypeptides. Finally, larger polypeptides comprisingtwo of the smaller peptide designs were also generated.

Exemplary polypeptides designed as described above are presented inTables 3-9, below. To provide greater clarity into the types ofpolypeptides that have been developed, the peptides have been organizedinto Classes. Typically, the striapathic region of a specific Class ofpolypeptides shares a common sequence of hydrophobic and hydrophilicmodules that is at least six or seven amino acid residues long. However,because the data indicates that polypeptides that have the same sequencebut reversed N-terminal to C-terminal orientation have surprisinglysimilar anti-inflammatory activities, efforts have been made to keepsuch polypeptides in the same Class. Accordingly, some polypeptides havebeen grouped into the same Class even though the common sequence ofhydrophobic and hydrophilic modules is less than six amino acid residueslong. In addition, some of the polypeptides could have been groupeddifferently because they contain the common sequence of hydrophobic andhydrophilic modules of more than one Class. Thus, while providing ahelpful framework for organizing the polypeptides around structural andfunctional similarities, the classification system does not capture allaspects of the relationships between different polypeptides.

Table 3 presents various Class I polypeptides, which have a striapathicregion that includes a sequence corresponding to Formula I (i.e.,Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)). Two different typesof Class I polypeptides are presented in Table 3: peptides that have astriapathic region consisting of a sequence corresponding to Formula II(i.e.,Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a));and peptide that have a striapathic region consisting of a sequencecorresponding to Formula III (i.e.,X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)).In addition, a peptide having a striapathic region having a sequencecorresponding to Formula I, but not Formulas II or III, is presented.

TABLE 3 Class I Polypeptides RelB Binding E RP # Sequence (kCal/mol)Formula SEQ ID NO: 394 NFNFFFRFFF −1,286.6 III 33 108 WWWRWWWEWQ−1,278.0 II 34 109 EFNFFFRFFF −1,247.7 III 35 110 DFEFFFRFFF −1,232.0III 36 111 QFEFFFRFFF −1,226.8 III 37 112 EFEFFFRFFF −1,216.0 III 38 113FFFRFFFEFQ −1,208.9 II 39 114 FFFRFFFEFE −1,176.3 II 40 115 FFFRFFFEFD−1,172.3 II 41 116 FFFRFFFNFE −1,162.6 II 42 117 FFFRFFFDFE −1,147.7 II43 118 FFFRFFFNFN −1,139.9 II 44 119 FFFHFFFEFQ −1,135.4 II 45 120FFFHFFFNFE −1,126.4 II 46 121 FFFHFFFEFN −1,126.4 II 47 122 EFNFFFHFFF−1,125.1 III 48 123 FFFRFFFEFN −1,124.5 II 49 125 FFFHFFFEFE −1,115.4 II50 126 QFEFFFHFFF −1,114.4 III 51 127 FFFHFFFEFD −1,114.3 II 52 128FFFHFFFDFE −1,111.4 II 53 129 YYYRYYYEYQ −1,110.2 II 54 130 NFEFFFHFFF−1,109.1 III 55 131 FFFKFFFKFE −1,107.0 II 56 133 EFDFFFRFFF −1,103.4III 57 135 FFFHFFFDFD −1,102.4 II 58 136 FFFHFFFNFN −1,100.4 II 59 137FFFRFFFDFD −1,100.3 II 60 138 FFFKFFFKFN −1,098.2 II 61 139 FFFKFFFEFE−1,095.1 II 62 140 FFFEFFFKFE −1,091.8 II 63 141 FFFQFFFQFQ −1,088.8 II64 143 FFFKFFFQFQ −1,084.4 II 65 144 FFFKFFFNFN −1,083.5 II 66 145FFFNFFFNFN −1,083.3 II 67 146 FFFKFFFEFQ −1,082.6 II 68 148 FFFKFFFKFQ−1,080.0 II 69 149 FFFKFFFQFK −1,079.6 II 70 150 FFFKFFFKFD −1,077.4 II71 152 FFFKFFFDFD −1,074.5 II 72 153 FFFNFFFKFN −1,074.2 II 73 154FFFDFFFDFD −1,073.5 II 74 155 FFFKFFFEFK −1,073.3 II 75 156 FFFKFFFDFK−1,072.6 II 76 157 FFFEFFFEFE −1,070.8 II 77 158 FFFDFFFKFD −1,070.7 II78 159 FFFKFFFKFK −1,070.7 II 79 160 FFFEFFFKFK −1,069.7 II 80 161FFFQFFFKFK −1,069.6 II 81 162 FFFKFFFNFK −1,069.2 II 82 163 FFFNFFFKFK−1,066.7 II 83 164 FFFQFFFKFQ −1,062.5 II 84 165 FFFDFFFKFK −1,061.9 II85 179 LLLRLLLELQ −966.7 II 86 395 FVFKFVFKFV −917.2 I 87 211 CCCRCCCECQ−818.2 II 88 230 MMMRMMMEMQ −774.6 II 89 232 VVVRVVVEVQ −771.6 II 90 258IIIRIIIEIQ −699.2 II 91 267 GGGRGGGEGQ −640.4 II 92 268 PPPRPPPEPQ−627.1 II 93 271 TTTRTTTETQ −614.4 II 94 273 AAARAAAEAQ −609.4 II 95 280AAAKAAAKAA −556.0 II 96 281 AAAEAAAEAE −541.6 II 97 287 SSSRSSSESQ−499.3 II 98

Table 4 presents some quasi-Class I polypeptides. These peptides includea sequence similar to the striapathic sequence of Formula II (i.e.,Y_(1a)-Y_(1b)-Y_(c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)),but the hydrophobic amino acid residues have all been replaced with aparticular hydrophilic amino acid residue.

TABLE 4 Quasi-Class I Polypeptides RelB Binding E RP # Sequence(kCal/mol) Formula SEQ ID NO: 173 HHHRHHHEHQ −1,002.2 II* 99 195RRRRRRRERQ −855.2 II* 100 275 QQQRQQQEQQ −575.6 II* 101 276 EEEREEEEEQ−569.5 II* 102 284 NNNRNNNENQ −522.7 II* 103 288 DDDRDDDEDQ −463.6 II*104 290 KKKRKKKEKQ −423.7 II* 105 *These peptides do not comply with thesequence requirements of Formula II, but instead represent an “allhydrophilic” variation on the sequence requirements of Formula II.

Table 5 presents various Class II, Sub-class 1 polypeptides. Thepresented peptides have a striapathic region consisting of a sequencecorresponding to Formula X (i.e.,Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2b)-X_(2b)-Y_(3a)-X_(3a)),or a striapathic region consisting of a sequence corresponding toFormula XI (i.e.,X_(1a)-Y_(1a)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)).

TABLE 5 Class II, Sub-class 1 Polypeptides RelB Binding E RP# Sequence(kCal/mol) Formula SEQ ID NO: 124 FFQKFFKRWR −1,121.3 X 106 132FFRKFFKRFR −1,104.8 X 107 134 RFRKFFKRFF −1,103.3 XI 108 142 RFRKFFKQFF−1,085.5 XI 109 147 FFQKFFKRFR −1,080.3 X 110 151 RWRKFFKQFF −1,077.0 XI111 166 FFEHFWKEFN −1,044.8 X 112 167 FFQHFWKQFN −1,024.9 X 113 168QFNHFFKEFF −1,022.8 XI 114 169 FFDKFFHDFQ −1,014.2 X 115 170 QFDHFFKDFF−1,011.9 XI 116 171 FFEKFFHNFQ −1,009.9 X 117 172 NFEKWFHEFF −1,007.9 XI118 175 LFRRAFKQLD −989.5 X 119 177 NFQKWFHQFF −976.3 XI 120 182KFRKAFKRFF −944.8 XI 121 183 FFRKFAKRFK −933.2 X 122 185 FFKKFFKKFK−920.6 X 123 186 KFKKFFKKFF −919.6 XI 124 424 KARKAFKRFF −910.2 XI 125190 WVKDAMQHLD −888.7 X 126 194 FFKKFAKKFK −859.1 X 127 198 FAEKFFKNFK−850.4 X 128 199 KFNKFFKEAF −847.1 XI 129 200 FAKQFFNKFK −846.0 X 130201 KFNKAFKQAF −837.8 XI 131 202 KFNKAFKQAF −837.8 XI 131 204 FAQKFFKDFK−835.9 X 133 206 FAEEFAEEFE −823.1 X 134 207 KFKKFFKKAF −820.7 XI 135209 KFKNFFQKAF −819.1 XI 136 210 KFKNFFQKAF −819.1 XI 136 212 FAKQFANKFK−817.9 X 138 213 KFKNAFQKAF −815.2 XI 139 214 KFKNAFQKAF −815.2 XI 139215 FAKKFFKKFK −814.0 X 141 216 KFKKAFKKFF −811.2 XI 142 218 FAEKFAEKFE−807.6 X 143 219 DLHQMADKVW −807.6 XI 144 425 KARKAAKRFF −800.3 XI 145225 FAKNFAKKFK −794.0 X 146 227 FAEKFAKNFK −786.6 X 147 233 KFKKAFKKAF−771.2 XI 148 234 FAKNFAKNFK −769.8 X 149 235 FAKEFAKEFE −768.9 X 150236 KFDKAFKQAF −766.2 XI 151 237 KFDKAFKQAF −766.2 XI 151 238 FAEKFAKKFK−765.1 X 153 239 FAEKFAEKFK −764.2 X 154 398 FAKKFAKKFK −760.3 X 155 241FAKNFAKNFN −758.7 X 156 242 FAQKFAKNFK −758.6 X 157 243 FANNFANNFN−755.2 X 158 244 FANNFANNFN −755.2 X 158 245 FANKFANKFN −754.0 X 160 246FANKFAKKFK −752.2 X 161 247 FAQKFAKDFK −750.7 X 162 250 FAKEFAKEFK−745.7 X 163 251 FANKFANKFK −739.7 X 164 252 KFDKFFKQAF −739.1 XI 165253 KFDKFFKQAF −739.1 XI 165 254 KFNKAFKEAF −738.4 XI 167 255 KFNKAFKEAF−738.4 XI 167 256 FAKEFAKKFK −702.8 X 169 426 KARKAAKRAF −634.5 XI 170427 KARKAAKRAA −578.1 XI 171 285 AAEEAAEEAE −511.6 X 172 387 AAKKAAKKAK−301.6 X 173

Table 6 presents polypeptides that fall into a variety of differentClasses, including: Class II peptides (having a striapathic region thatincludes a sequence corresponding to any of Formulas VI to XVI); ClassII, Sub-class 2 (having a striapathic region that includes a sequencecorresponding to Formulas VIII and XII); Class II, Sub-class 3 (having astriapathic region that includes a sequence corresponding to FormulaIX); Class II, Sub-class 4 (having a striapathic region that includes asequence corresponding to Formulas XIV and XV); Class II, Sub-class 5(having a striapathic region that includes a sequence corresponding toFormulas XIII and XVI); Class III peptides (having a striapathic regionthat includes a sequence corresponding to any of Formulas XVII to XX);Class III, Sub-class 1 peptides (having a striapathic region thatincludes a sequence corresponding to Formulas XIX or XX); Class IVpeptides (having a striapathic region that includes a sequencecorresponding to Formulas IV and V); Class V peptides (having astriapathic region that includes a sequence corresponding to FormulaXXI); Class VI peptides (having a striapathic region that includes asequence corresponding to Formulas XXII and XXIII); Class VII peptides(having a striapathic region that includes a sequence corresponding toany of Formulas XXIV to XXVI); Class VIII peptides (having a striapathicregion that includes a sequence corresponding to any of Formulas XXVIIto XXXII): Class VIII, Sub-class 3 and 4 peptides (having a striapathicregion that includes a sequence corresponding to Formulas XXXI andXXXII, respectively); Class IX peptides (having a striapathic regionthat includes a sequence corresponding to any of Formulas XXXIII toXXXVIII); Class IX, Sub-class 3 and 4 peptides (having striapathicregions that include a sequence corresponding to Formulas XXXVII andXXXVIII, respectively); and Class XIII (having a striapathic region thatincludes a sequence corresponding to Formula L). Because polypeptides ofClass VIII, Sub-class 3 and Class IX, Sub-class 3 share the samesequence of hydrophobic and hydrophilic modules, but reversed N-terminalto C-terminal orientation, they could have been grouped into the sameClass and Sub-class. Similarly, because polypeptides of Class VIII,Sub-class 4 and Class IX, Sub-class 4 share the same sequence ofhydrophobic and hydrophilic modules, but reversed N-terminal toC-terminal orientation, they could have been grouped into the same Classand Sub-class.

TABLE 6 Class II to Class IX and Class XIII Polypeptides RelB Binding ERP # Sequence (kCal/mol) Formula SEQ ID NO: 396 FVKFVKFVKF −1,039.7 L174 405 KRKAFRKFFF −1,026.6 XIV 175 174 LHKMYNQVW −1,000.2 VII 176 176WVQNYMKHL −979.3 VII 177 178 RLVEMMRQIW −972.2 XX 178 180 FLKRLLQEI−955.9 VII 179 181 LRLLHRLL −950.2 XVII 180 184 WVRDSMKHL −925.6 VII 181408 KFFRKKFRFA −917.4 XXII 182 187 WVQRVVEKFL −906.4 IX 183 416AFFRRFKFKK −904.1 XXV 184 188 LFKEVVRQVW −902.9 IX 185 189 MDKIYDQVWK−893.3 VIII 186 388 FVKKFVKKFV −891.9 X 187 417 KKFKFRRFFA −888.8 XXVI188 191 WVRDVVRSMD −874.1 XIX 189 192 ELSNIYERVW −872.4 XX 190 193WIQRMMEVLR −866.9 XIX 191 404 FFFKRFAKRK −856.7 XV 192 196 LHKMSDRVW−852.4 VII 193 197 WVREYINSLE −851.2 XIX 195 402 FFKKRFAFRK −851.0 XXXI196 203 KWVQDYIKDM −837.0 XII 197 409 AFRFKKRFFK −832.7 XXIII 198 205LLRHLLRL −830.0 XVII 199 208 WIKKLLESSQ −819.7 XIX 200 217 DMSRVVDRVW−810.4 XX 201 220 FEEEFEEEFE −804.8 V 202 221 WVKNSINHL −803.7 VII 203222 LTKKGRRFC −799.7 XXI 204 223 IEQLLRKLF −796.8 VII 205 224 LHNISNKVW−794.5 VII 206 226 CFRRGKKTL −786.7 XXI 207 229 IVRRADRAAV −781.5 XXI208 231 TVERFKNLS −771.8 XXI 209 240 QSSELLKKIW −761.9 XX 210 248SLNKFREVT −750.5 XXI 211 249 LIKQIVKKLF −750.5 IX 212 397 FAKKFAKKF−739.3 VII 194 415 KKKFFF −706.8 XXVII 213 257 LYKKIIKKLL −699.8 IX 214259 FKKKFKKKFK −686.5 V 215 260 VAARDARRVI −684.6 XXI 216 261 FLKKVIQKIL−679.4 IX 217 262 LIKEIIKQVM −668.4 IX 218 263 LLKKIIKKYL −666.7 IX 219264 AFFEEEAEFE −652.2 XXXVIII 220 265 KKWVQDSMK −650.1 XVIII 221 266NFANKVQEVA −644.1 XXI 222 269 AVEQVKNAFN −621.1 XXI 223 272 MVQKIIEKIL−613.1 IX 224 274 KMSDQVWKK −595.9 XVIII 225 277 MVKKIIEKM −569.2 VII226 278 ALKKQVIKKI −559.1 XVI 227 279 IKKIVQKKLA −556.7 XIII 228 282AFFKKKAKFK −537.6 XXXVIII 229 283 MKEIIKVM −533.1 VII 230 286 AEEEAEEEAE−504.4 V 231 289 AKKKAKKKAK −431.6 V 232 414 KKKAAA 0.0 XXVII 233

Table 7 presents polypeptide of Classes VIII through XI. All of thepeptides presented in Table 7 have a striapathic region that includes ahydrophilic module having four or five hydrophilic amino acid residuesand/or a hydrophobic module having four or five hydrophobic amino acidresidues. Class VIII, Sub-class 1 peptides have a striapathic regionthat includes a sequence corresponding to Formulas XXVIII or XXIX; ClassVIII, Sub-class 2 peptides have a striapathic region that includes asequence corresponding to Formula XXX; Class IX, Sub-class 1 peptideshave a striapathic region that includes a sequence corresponding toFormulas XXXIV or XXXV; Class IX, Sub-class 2 peptides have astriapathic region that includes a sequence corresponding to FormulaXXXVI; Class X peptides have a striapathic region that includes asequence corresponding to any of Formulas XXXIX to XLIII; and Class XIpeptides have a striapathic region that includes a sequencecorresponding to any of Formulas XLIV to XLVIII. Because polypeptides ofClass VIII, Sub-class 1 and Class IX, Sub-class 1 share the samesequence of hydrophobic and hydrophilic modules, but reversed N-terminalto C-terminal orientation, they could have been grouped into the sameClass and Sub-class. Similarly, because polypeptides of Class VIII,Sub-class 2 and Class IX, Sub-class 2 share the same sequence ofhydrophobic and hydrophilic modules, but reversed N-terminal toC-terminal orientation, they could have been grouped into the same Classand Sub-class.

TABLE 7 Class VIII to XI Polypeptides RelB Binding E RP # Sequence(kCal/mol) Formula SEQ ID NO: 406 KRKKRFAFFF −993.5 XXX 234 422RKRKFFAFFK −948.2 XLVIII 235 407 FFFAFRKKRK −914.7 XXXVI 236 400FRKKRFAFFK −900.5 XXIX 237 419 FFFRRKKKFA −881.9 XLII 238 401 KFFAFRKKRF−880.1 XXXV 239 423 KFFAFFKRKR −877.1 XLV 240 411 KKKKKFFFFF −863.7 XXX241 418 AFKKKRRFFF −854.1 XLI 242 428 KRKKRAAFFF −842.0 XXX 243 420KKFFAFFRKR −840.2 XLVI 244 421 RKRFFAFFKK −835.5 XLVII 245 429KRKKRAAAFF −758.1 XXX 246 413 KKKKFFFF −715.8 XXVIII 247 430 KRKKRAAAAF−676.7 XXX 248 270 KKKAFFFAKK −614.4 XLVII 249 431 KRKKRAAAAA −544.9 XXX250 410 KKKKKAAAAA −385.3 XXX 251 412 KKKKAAAA −382.8 XXVIII 252

Table 8 presents polypeptides of Class XII and Class XIV. Class XIIpeptides have a striapathic region that includes a sequencecorresponding to Formula XLIX (i.e.,Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)). Class XII peptides arepredicted to adopt a beta-strand secondary structure. Class XIV peptidesare proline-rich peptides that have a striapathic region that includes asequence corresponding to one of Formulas LI-LIV.

TABLE 8 Beta-Strand and Proline-Rich Polypeptides RelB Binding E RP #Sequence (kCal/mol) Formula SEQ ID NO: 393 FKFKFKFKF −1,193.2 XLIX 253391 FRFKFKFR −1,190.8 XLIX 254 392 RFQFKFRF −1,170.3 XLIX 255 390FRFKFKF −1,083.3 XLIX 256 389 FRFKFA −1,009.8 XLIX 257 449 RRFPRPPFF−1,116.8 LI 258 450 FFPPRPFRR −1,100.0 LII 259 448 LYPPRPFRR −1,059.3LII 260 447 RRIPRPPYL −1,050.5 LI 261 452 PFRPPPRPRF −1,012.2 LIII 262451 PRPRPPPRFF −1,002.1 LIV 263 444 FFPPKPFKK −954.8 LII 264 441KKIPKPPYL −922.1 LI 265 446 PFKPPPKPKP −882.3 LIII 266 445 PKPKPPPKFP−866.3 LIV 267 442 LYPPKPIKK −846.6 LII 268 443 KKFPKPPFF −802.8 LI 269

Table 9 presents fusion peptides, which include combinations of Class I,Class II, and/or Class III peptides linked together by a peptide bondand, optionally, a short peptide linker (e.g., a tri-glycine (GGG)linker).

TABLE 9 Peptide Combinations RelB Binding E RP # Sequence (kCal/mol)Formula SEQ ID NO: 292 EFEFFFRFFFGGGEFEFFFRFFF −1,606.1 III + III 270293 QFEFFFRFFFGGGQFEFFFRFFF −1,602.0 III + III 271 294DFEFFFRFFFGGGDFEFFFRFFF −1,591.8 III + III 272 295EFNFFFRFFFGGGEFNFFFRFFF −1,591.8 III + III 273 296 FFFRFFFEFQFFFRFFFEFQ−1,511.6 II + II 274 297 FFFRFFFEFQGGGFFFRFFFEFQ −1,511.5 II + II 275298 RWRKFFKRFFQFEFFFRFFF −1,505.2 XI + III 276 299RWRKFFKRFFGGGFFFRFFFNFN −1,501.3 XI + II 277 300 RFRKFFKRFFQFEFFFRFFF−1,486.0 XI + III 278 301 RFRKFFKRFFGGGFFFRFFFNFN −1,485.0 XI + II 279302 RWRKFFKRFFGGGFFFRFFFEFQ −1,479.6 XI + II 280 303RFRKFFKRFFGGGFFFRFFFEFQ −1,476.8 XI + II 281 304 EFEFFFRFFFEFEFFFRFFF−1,476.0 III + III 282 305 RWRKFFKRFFNFNFFFRFFF −1,474.2 XI + III 283306 QFEFFFRFFFQFEFFFRFFF −1,467.0 III + III 284 307RWRKFFKRFFGGGNFNFFFRFFF −1,464.2 XI + III 285 308 EFNFFFRFFFEFNFFFRFFF−1,460.5 III + III 286 309 RFRKFFKRFFNFNFFFRFFF −1,458.4 XI + III 287310 FFRKFFKRFRGGGNFNFFFRFFF −1,447.1 X + III 288 311RFRKFFKRFFGGGNFNFFFRFFF −1,432.1 XI + III 289 312 DFEFFFRFFFDFEFFFRFFF−1,430.0 III + III 290 313 RWRKFFKRFFFFFRFFFEFQ −1,427.4 XI + II 291 314RFRKFFKRFFFFFRFFFEFQ −1,425.6 XI + II 292 315 FFRKFFKRFRGGGFFFRFFFNFN−1,420.6 X + II 293 316 FFRKFFKRWRGGGFFFRFFFNFN −1,417.5 X + II 294 317RFRKFFKRFFFFFRFFFNFN −1,406.6 XI + II 295 318 FFRKFFKRFRFFFRFFFEFQR−1,402.0 X + II 296 291 FFEHFWKEFNGGGNFQKWFHQFF −1,401.6 X + XI 297 319FFRKFFKRWRQFEFFFRFFF −1,400.7 X + III 298 320 RWRKFFKRFFFFFRFFFNFN−1,397.9 XI + II 299 321 NFQKWFHQFFGGGFFEHFWKEFN −1,396.0 XI + X 300 322FFRKFFKRWRGGGNFNFFFRFFF −1,394.4 X + III 301 323 FFRKFFKRWRFFFRFFFEFQR−1,394.3 X + II 302 324 FFRKFFKRWRNFNFFFRFFF −1,393.7 X + III 303 325FFRKFFKRFRGGGFFFRFFFEFQR −1,386.8 X + II 304 326 FFRKFFKRFRQFEFFFRFFF−1,382.8 X + III 305 327 FFRKFFKRFRNFNFFFRFFF −1,378.2 X + III 306 328RFRKFFKRFFGGGQFEFFFRFFF −1,368.5 XI + III 307 329FFRKFFKRWRGGGFFFRFFFEFQR −1,354.5 X + II 308 330 FFRKFFKRFRGGGQFEFFFRFFF−1,352.8 X + III 309 331 FFRKFFKRWRGGGQFEFFFRFFF −1,352.2 X + III 310332 RWRKFFKRFFGGGQFEFFFRFFF −1,349.8 XI + III 311 333QFNHFFKEFGGGQFNHFFKEFF −1,340.0 VII + XI 312 334 FFRKFFKRFRFFFRFFFNFN−1,337.5 X + II 313 335 FFRKFFKRWRFFFRFFFNFN −1,337.0 X + II 314 336FFEHFWKEFNGGGFFEHFWKEFN −1,325.5 X + X 315 337 FFEHFWKEFGGGNFQKWFHQFF−1,324.8 VII + XI 316 338 NFQKWFHQFGGGFFEHFWKEFN −1,317.9 VII + X 317339 FFEHFWKEFNGGGLHKMYNQVW −1,315.4 X + VII 318 340NFQKWFHQFFGGGNFQKWFHQFF −1,309.9 XI + XI 319 341 FAKKFAKKFKGGGNFQKWFHQFF−1,308.3 X + XI 320 342 FFEKFFHNFQGGGFFEKFFHNFQ −1,304.6 X + X 321 343FFQHFWKQFNGGGFFQHFWKQFN −1,300.2 X + X 322 344 NFQKWFHQFFNFQKWFHQFF−1,293.5 XI + XI 323 345 FAKKFAQKFKGGGNFQKWFHQFF −1,291.9 X + XI 324 346FAKKFAKKFKGGGQFEFFFRFFF −1,290.9 X + III 325 347 QFNHFFKEFQFNHFFKEFF−1,279.8 VII + XI 326 348 FAKKFAKKFKGGGDFEFFFRFFF −1,278.4 X + III 327349 FFEHFWKEFNGGGWVQNYMKHL −1,268.8 X + VII 328 350 FAKKFAKKFKQFEFFFRFFF−1,268.5 X + III 329 351 FFQHFWKQFNFFQHFWKQFN −1,263.2 X + X 330 352FFEHFWKEFNFFEHFWKEFN −1,251.5 X + X 331 353 NFEKWFHEFFNFEKWFHEFF−1,247.0 XI + XI 332 354 FAKKFAKKFKGGGQFNHFFKEFF −1,244.6 X + XI 333 355NFEKWFHEFFGGGNFEKWFHEFF −1,241.4 XI + XI 334 356 FAKKFAKKFKGGGFFFRFFFEFQ−1,237.9 X + II 335 357 FAKKFAKKFKDFEFFFRFFF −1,235.3 X + III 336 358QFNHFFKEFFGGGQFNHFFKEFF −1,230.0 XI + XI 337 359 FAKKFAKKFKGGGEFEFFFRFFF−1,221.7 X + III 338 360 FAKKFAKKFKGGGEFNFFFRFFF −1,221.0 X + III 339361 FAKKFAKKFKGGGNFEKWFHEFF −1,212.3 X + XI 340 362FAKKFAKKFKGGGFFEKFFHNFQ −1,210.8 X + X 341 363 QFNHFFKEFFQFNHFFKEFF−1,208.6 XI + XI 342 364 FFEKFFHNFQFFEKFFHNFQ −1,207.5 X + X 343 365FAKKFAKKFKEFEFFFRFFF −1,204.2 X + III 344 366 FAKKFAKKFKEFNFFFRFFF−1,187.6 X + III 345 367 FAKKFAKKFKFFEHFWKEFN −1,168.1 X + X 346 368FAKKFAKKFKFFFRFFFEFQ −1,166.4 X + II 347 369 FAKKFAKKFKLHKMYNQVW−1,159.5 X + VII 348 370 FAKKFAKKFKGGGFFEHFWKEFN −1,140.4 X + X 349 371FAKKFAKKFKGGGWVQNYMKHL −1,130.4 X + VII 350 372 FAKKFAKKFKNFQKWFHQFF−1,126.1 X + XI 351 373 FAKKFAKKFKFFQHFWKQFN −1,119.8 X + X 352 374FAKKFAKKFKGGGFFQHFWKQFN −1,119.6 X + X 353 375 FAKKFAKKFKWVQNYMKHL−1,119.2 X + VII 354 376 FAKKFAKKFKQFNHFFKEFF −1,108.3 X + XI 355 377FAKKFAKKFKGGGLHKMYNQVW −1,100.3 X + VII 356 378 FAKKFAKKFKNFEKWFHEFF−1,081.4 X + XI 357 379 FAKKFAKKFKFFEKFFHNFQ −1,046.8 X + X 358 380FAKKFAKKFKGGGAFFKKKAKFK −950.9 X + 359 XXXVIII 381AFFKKKAKFKGGGAFFKKKAKFK −935.5 XXXVIII + 360 XXXVIII 382KFKKAFKKAFKFKKAFKKAF −925.2 XI + XI 361 383 KFKKAFKKAFGGGKFKKAFKKAF−923.8 XI + XI 362 384 FAKKFAKKFKGGGFAKKFAKKFK −909.2 X + X 363 385FAKKFAKKFKAFFKKKAKFK −839.9 X + 364 XXXVIII 228 PSRKSMEKSVAKLLNKIAKSEP−782.4 IX + XVIII 365 386 AFFKKKAKFKAFFKKKAKFK −716.0 XXXVIII + 366XXXVIII

In each of Tables 3-9, the RP# is a randomly assigned designation usedto identify specific peptide sequences. The “Binding E” (see column 3 ineach of the Tables) corresponds to a predicted measure of the energyreleased when individual peptides bind to the protein dimerizationdomain of RelB, an NFkB Class II protein (see Example 2, below).

Example 2 Predicted Binding of Peptides to Rel B

To identify peptides having anti-inflammatory activity, the NF-kBcomplex was selected as a target, since it is known to be a keycomponent in the signaling pathways that regulate inflammation.Dimerization of NF-kB (either homologous or heterologous), which ismediated by the dimerization domains found in NF-kB Class II proteins(e.g., RelA, RelB, cRel, NF-kB1, and NF-kB2), is essential foractivation of the NF-kB complex and its generation of pro-inflammatorysignals. Accordingly, peptide designs were selected for their ability tospecifically bind to the dimerization domain of RelB (NCBI Acc. No.NP_033072.2), with the goal that such binding would inhibit NF-kBdimerization and activation.

Peptide binding to the dimerization domain of Rel B was evaluated insilico, using the web-based ClusPro™ algorithm developed at BostonUniversity. The ClusPro™ algorithm filters docked conformations betweena protein target and a putative ligand and determines surfacecomplementarity, ranking the conformations based on their clusteringproperties. The free energy filters select complexes with the lowestdesolvation and electrostatic energies. Clustering is then used tosmooth the local minima and to select the ones with the broadest energywells, a property associated with the free energy at the binding site.Using this method, it is possible to evaluate the affinity a ligandpossesses for a particular target, whereupon the ligands can be rankedand then tested for biological activity in vitro or in vivo.

The binding energies calculated by the ClusPro™ algorithm are shown foreach of the peptides in Tables 3-9, in the third columns of the tables.In each of Tables 3-9, the peptides are ranked according to thecalculated RelB binding energy, from highest to lowest binding energy.The RelB binding energies were used to explore the structure-functionrelationship of the peptides, particularly with regard to (i) increasingor decreasing hydrophobicity, (ii) positive/negative charge density, and(iii) altering the arc of the hydrophobic and hydrophilic faces of thepeptides. The peptides shown in Table 10 (below) will be used toillustrate the results of the study.

TABLE 10 Predicted Binding of Select Peptides to RelB RelB Binding E SEQID RP# Sequence (kCal/mol)* Formula NO: RP-182 KFRKAFKRFF −944.8 XI 121RP-166 FFEHFWKEFN −1,044.8 X 112 RP-113 FFFRFFFEFQ −1,208.9 II 39 RP-289AKKKAKKKAK −431.6 V 232 RP-387 AAKKAAKKAK −338.3 X 173 NF-CONTR2IESKRRKKKP −476.6 N/A 382 NF-CONTR3 APGPGDGGTA −621.1 N/A 383 *The lowerthe energy value, the greater affinity the ligand possesses for thebinding site on the target protein.

A structural model of the RelB subunit of NF-kB is shown in FIG. 1.Amino acids with the dimerization site are shaded to indicate theirhydrophobic or hydrophilic character. In particular, the amino acidresidues colored magenta are hydrophilic, while the amino acid residuescolored cyan are hydrophobic. Given the distinct locations of thehydrophilic and hydrophobic amino acid residues within the bindingpocket of the dimerization domain, it is evident that striapathicpeptides having an amphipathic secondary structure have the potential tobind site-specifically to the dimerization domain binding pocket.

The secondary structure of RP-182 (SEQ ID NO: 121) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 2. As can be seen in the panelson the right, RP-182's predicted secondary structure has distincthydrophobic and hydrophilic sides that comprise approximately equalfacial arcs (see also FIG. 9) and are of high volume. Overall, thestructure of RP-182 possesses high hydrophobicity and high cationicity(with a total of five cationic amino acid residues). Thesecharacteristics of RP-182 are summarized in Table 11, below. Based onthe structural modeling, RP-182 binds with high affinity to the RelBdimerization domain binding pocket, with an estimated binding energy of−944.8 kcal/mol.

The secondary structure of RP-166 (SEQ ID NO: 112) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 3. As can be seen in the panelson the right, RP-166's predicted secondary structure also has distincthydrophobic and hydrophilic sides that comprise approximately equalfacial arcs (see also FIG. 9). These characteristics are not surprising,as the striapathic region of RP-166 has a modular structure that isidentical (albeit reversed) to that of RP-182's (compare Formulas X andXI). As with RP-182, the hydrophobic and hydrophilic surfaces of RP-166are of high volume, but RP-166 has a greater ratio of hydrophobic volumeto hydrophilic volume as compared to RP-182. In addition, thecationicity of RP-166 is significantly reduced relative to that ofRP-182, since RP-166 has an equal number of cationic amino acid residuesand anionic amino acid residues. These characteristics of RP-166 aresummarized in Table 11, below. Based on the structural modeling, RP-166binds to the RelB dimerization domain binding pocket with even higheraffinity than RP-182, having an estimated binding energy of −1,044.8kcal/mol.

The secondary structure of RP-113 (SEQ ID NO: 39) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 4. As can be seen in the panelson the right, RP-113's predicted secondary structure also has distincthydrophobic and hydrophilic sides, but the hydrophobic side comprises amuch larger facial arc than the hydrophilic side. As shown in FIG. 9,the facial arc of the polar side of RP-113 is only 60°, while the facialare of the non-polar side is 300°. Consistent with this shift toward alarger hydrophobic surface, RP-113 has a larger hydrophobic volume thaneither RP-182 or RP-166, as well as a significantly larger ratio ofhydrophobic to hydrophilic volume. See Table 11, below. Like RP-166, thecationicity of RP-113 is significantly reduced relative to that ofRP-182, since RP-113 has an equal number of cationic amino acid residuesand anionic amino acid residues. Based on the structural modeling,RP-113 binds to the RelB dimerization domain binding pocket with one ofthe highest affinities predicted for the peptides of the invention,having an estimated binding energy of −1,208.9 kcal/mol.

The secondary structure of RP-387 (SEQ ID NO: 173) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 5. As can be seen in the panelson the right, RP-387's predicted secondary structure has distincthydrophobic and hydrophilic sides. However, in contrast to RP-113, thehydrophilic side of RP-387 comprises a much larger facial arc than thehydrophobic side. As shown in FIG. 10, the facial are of the polar sideof RP-387 is 245°, while the facial arc of the non-polar side is 115°.Consistent with this shift toward a larger hydrophilic surface, RP-387has a smaller hydrophobic volume than any of RP-182, RP-166, and RP-113,as well as a significantly smaller ratio of hydrophobic to hydrophilicvolume. See Table 11, below. With regard to cationicity, RP-387 issimilar to RP-182, having a total of five cationic amino acid residues.Based on the structural modeling. RP-387 binds to the RelB dimerizationdomain binding pocket, but is does so relatively poorly, having anestimated binding energy of only −338.3 kcal/mol.

The secondary structure of RP-289 (SEQ ID NO: 232) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 6. As can be seen in the panelson the right, RP-289's predicted secondary structure has distincthydrophobic and hydrophilic sides. However. RP-289's hydrophobic side isone of the smallest of the peptides screened. As shown in FIG. 9, thefacial arc of the polar side of RP-289 is 290°, while the facial arc ofthe non-polar side is only 70°. Of the peptides listed in Table 11,RP-289 has the smallest hydrophobic volume and the smallest ratio ofhydrophobic to hydrophilic volume. RP-289 also has the highestcationicity of the peptides listed in Table 11, having a total of sevencationic amino acid residues. Based on the structural modeling, RP-289binds to the RelB dimerization domain, though comparatively much moreweakly than RP-182, RP-166, and RP-113, having an estimated bindingenergy of only −431.6 kcal/mol.

Tables 10 and 11 also identify two control peptides, NF-CONTR2 andNF-CONTR3, which are fragments of the RelB subunit of NF-kB. Thesequences of NF-CONTR2 and NF-CONTR3 do not conform to any of structuralFormulas I-LIII. The secondary structure of NF-CONTR2 (SEQ ID NO: 382)and its binding to RelB (SEQ ID NO: 367) is modeled in FIG. 7. Thesecondary structure of NF-CONTR3 (SEQ ID NO: 383) and its binding toRelB (SEQ ID NO: 367) is modeled in FIG. 8. Neither peptide is predictedto adopt a clearly amphipathic secondary structure throughout the lengthof the peptide. Moreover, although the ClusPro™ algorithm identifies abinding interaction between each of NF-CONTR2 and NF-CONTR3 and RelB,the binding energies are not very strong and neither peptide displays apreference for binding to the RelB dimerization domain binding pocket.

TABLE 11 Physical Characteristics of Select Peptides HPB SEQ RelB Vol/ID Binding HPL HPB HPL tH tH tH HPB/ RP# Sequence NO: Energy (+) (−) VolVol Vol HPL HPB tH HPL 182 KFRKAFKRFF 121 −944.8 6 1 696.9 659.8 0.95−50.8 16.4 −0.32 166 FFEHFWKEFN 112 −1,044.8 3 3 637.7 775.0 1.22 −33.016.7 −0.51 113 FFFRFFFEFQ 39 −1,208.9 2 2 414.5 1030.4 2.49 −23.5 25.9−1.10 289 AKKKAKKKAK 232 431.6 8 1 896.8 213.3 0.24 −61.6 4.8 −0.08 387AAKKAAKKAK 173 −338.3 6 1 640.5 355.5 0.55 −44.0 8.0 −0.18 NF-C2IESKRRKKKP 382 −476.6 7 2 954.9 297.4 0.31 −66.8 3.5 −0.05 NF-C3APGPGDGGTA 383 −621.1 1 1 115.1 665.7 5.78 −9.2 8.0 −0.87 *Bindingenergies are in kcal/mol. Volumes are in cubic angstroms. HPL meanshydrophilic; HPB means hydrophobic. “tH” is the total hydrophobicity (inkcal/mol), as defined by Engleman et al. (1986), “Identifying nonpolartransbilayer helices in amino acid sequences of membraneproteins,” Annu. Rev. Biophys. Bioeng. 15: 321-53.

FIGS. 1 through 10 and Table 11 reveal some important aspects of thestructure-function relationship for the peptides of the invention.First, all of the peptides that are predicted to bind the RelBdimerization domain binding pocket have an amphipathic secondarystructure. Second, greater hydrophobic volume, a greater ratio ofhydrophobic to hydrophilic volume, and a greater hydrophobic arc are allassociated with increased affinity for the binding pocket of the RelBdimerization domain. Third, increased cationicity is associated withdecreased binding affinity for the binding pocket of the RelBdimerization domain.

Table 4, which lists some “all hydrophilic” variants of the Class Ipeptides, appears to potentially refute the conclusion that increasedcationicity is associated with decreased binding affinity for thebinding pocket of the RelB dimerization domain. In each of the peptidesin Table 4, the hydrophobic residues of a Class I, Formula II peptidehave been replaced with a single type of hydrophilic residue.Significantly, RP-173 (HHHRHHHEHQ; SEQ ID NO: 99) and RP-195(RRRRRRRERQ; SEQ ID NO: 100) both have a high affinity for the bindingpocket of the RelB dimerization domain (−1,002.2 and −855.2 kcal/mol,respectively), despite have eight amino acid residues that generallyhave a cationic charge in solution. Because both histidine and argininehave large side chains, a potential explanation for their high RelBbinding affinities is that the uncharged hydrocarbon groups in the sidechains provide some hydrophobicity that would otherwise have been lostby switching from a hydrophobic residue to a hydrophilic residue. Inaddition, when bound to RelB, some of the histidine and arginineresidues may adopt an uncharged state. Table 4 therefore sheds furtherlight on the structure-function relationship of the peptides of theinvention by indicating that histidine and arginine can function in aquasi-hydrophobic capacity, at least with regard to the bindingaffinities of peptides for the RelB dimerization domain binding pocket.Accordingly, in some peptides of the invention, it can be energeticallyadvantageous to place a histidine or arginine adjacent to a hydrophobicmodule that is made up of one or two hydrophobic amino acid residues.

Example 3 RelB Amino Acid Residues Involved in Peptide Binding

A model of the amino acid residues that line the binding pocket of theRelB dimerization domain is shown in FIG. 11. The model shows thatGlu-298, Asp-330, and His-332 are key hydrophilic amino acid residuesthat line the binding pocket, while Tyr-300, Leu-301, Leu-302, andLeu-371 are important hydrophobic residues. The same model, with theaddition of a stick diagram of the RP-182 peptide (SEQ ID NO: 121) isshown in FIG. 12. The dotted lines in FIG. 12 show ionic bonds between(1) Lys-7 of RP-183 and Asp-330 of RelB, and (2) Lys-4 of RP-183 andGlu-298 of RelB. Further stabilizing the interaction is an intra-ionicbond formed between Arg-8 of RP-183 and the carboxy terminal Lys-10 ofRP-183. In addition to the ionic binds, there are numerous Van der Waalsinteractions. For the sake of clarity, only that of Phe-9 of RP-182 withLeu-371 of Rel-B is shown. However, the other hydrophobic amino acidresidues on the hydrophobic face of RP-183 interact with the hydrophobic“floor” of the cleft of dimerization site of Rel-B.

An analysis of the ionic and Van der Waals interactions involved withthe binding of different peptides of the invention has revealed that thepeptides bind to a subset of the RelB amino acid residues selected fromthe group consisting of Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300,Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, Ala-329, Asp-330, Val-331,His-332, Gln-334, and Leu-371. See Table 13, below. Tyr-300, Leu-302,and His-332 are designated in the literature as being critical fordimerization. The amino acids most critical to binding by peptides ofthe invention include Glu-298, Tyr-300. Leu-302, Asp-330, Gln-334, andLeu-371.

Example 4 Binding of Peptides to Protein Targets Other than RelB

A subset of the peptides shown in Tables 3-9 were further evaluated insilico to determine whether they bind to signaling proteins involved inthe inflammatory response other than RelB. In doing so, it wasdiscovered the dimerization cleft of the RelB subunit of NF-kB hasstructural parallels in a number of other signaling molecules.Consistent with these structural parallels, the peptides of theinvention are predicted (by the ClusPro™ algorithm) to bind with highaffinity to important signaling molecules in the inflammatory cascade,including: TGFβ (NCBI Acc. No. NP_000651.3; SEQ ID NO: 368); Notch1(GenBank Acc. No. AAG33848.1; SEQ ID NO: 369); Wnt8R (NCBI Acc. No.XP_005214377.1; SEQ ID NO: 370); TRAIL (GenBank Acc. No. EAW78466.1; SEQID NO: 371); IL6R (NCBI Acc. No. NP_786943.1; SEQ ID NO: 372); IL10R(NCBI Acc. No. NP_001549.2; SEQ ID NO: 373); EGFR (GenBank Acc. No.AAR85273.1; SEQ ID NO: 374); and CDK6 (NCBI Acc. No. NP_001250.1; SEQ IDNO: 375). Representative peptides of the invention and the predictedbinding energies between the peptides and each of these signalingmolecules is shown in Tables 12A and 12B, below.

TABLE 12A Predicted Binding of Select Peptides to Different InflammatoryTargets SEQ ID RP# Sequence NO: RelB TGFβ NOTCH1 WNT8R TRAIL 185FFKKFFKKFK 123 920.6 −880.1 −817.7 −747.2 −904.5 186 KFKKFFKKFF 124−919.6 −846.0 −887.7 −739.1 −884.3 183 FFRKFAKRFK 122 −933.2 −878.9−890.8 −763.1 −938.8 182 KFRKAFKRFF 121 −944.8 −851.8 −1,096.3 −733.7−938.8 118 FFFRFFFNFN 44 −1,139.9 −1,074.7 −1,032.4 −990.9 −995.4 394NFNFFFRFFF 33 −1,286.6 −1,002.6 −1,059.6 −971.2 −943.8 389 FRFKFA 257−1,009.8 −878.4 −846.4 −804.5 −916.8 390 FRFKFKF 256 −1,083.3 −933.2−1,005.3 −871.0 −1,014.4 391 FRFKFKFR 254 −1,190.8 −987.5 −1,005.4−897.9 −1,049.2 392 RFQFKFRF 255 −1,170.3 −943.2 −923.1 −853.8 −1,039.6387 AAKKAAKKAK 173 −301.6 −397.7 −385.5 −394.9 −397.7 *All bindingaffinities are in kcal/mol.

TABLE 12A Predicted Binding of Select Peptides to Different InflammatoryTargets SEQ ID RP# Sequence NO: RelB EGFR IL6R IL10R CDK6 185 FFKKFFKKFK123 −920.6 −785.4 −747.5 −756.3 −753.9 186 KFKKFFKKFF 124 −919.6 −866.3−755.0 −742.0 −718.1 183 FFRKFAKRFK 122 −933.2 −795.6 −696.7 −738.6−783.0 182 KFRKAFKRFF 121 −944.8 −853.8 −784.5 −785.9 −781.5 118FFFRFFFNFN 44 −1,139.9 −1,039.4 −1,074.8 −881.4 −1,020.8 394 NFNFFFRFFF33 −1,286.6 −1,061.4 −1,069.9 −850.8 −1,075.3 389 FRFKFA 257 −1,009.8−896.0 −812.3 −779.2 −900.5 390 FRFKFKF 256 −1,083.3 −1,036.3 −952.2−876.2 −861.1 391 FRFKFKFR 254 −1,190.8 −1,024.9 −957.6 −882.3 −899.9392 RFQFKFRF 255 −1,170.3 −1,010.4 −1,052.3 −901.7 −870.0 387 AAKKAAKKAK173 −301.6 −395.9 −342.0 −338.1 −351.4

The data reveals that the strength of binding to RelB is highlycorrelated with the strength of binding to the various inflammatorytargets. In other words, peptides that are predicted to bind with highaffinity to RelB are likewise predicted to bind with high affinity toTGFβ, Notch1, Wnt8R, TRAIL, EGFR, IL6R, and IL10R.

A closer evaluation of the predicted binding interactions between thepeptides of the invention and each of TGFβ, Notch1, Wnt8R, TRAIL, EGFR,IL6R, and IL10R reveals that the peptides not only bind with highaffinity, but also bind to functionally critical sites on the targets.For example, peptides of the invention are predicted to bind to thereceptor-binding site on TGFβ, the calcium-binding site on Notch1, theWnt8-binding site on Wnt8R, the receptor-binding site on TRAIL, theIL6-binding site on IL6R, the IL10-binding site on IL10R, and thegeneral ligand-binding site on EGFR. A non-exhaustive list of amino acidresidues in each of these targets that are bound by the peptides of theinvention is shown in Table 13.

TABLE 13 Amino Acid Residues in Target Proteins Contacted by Peptides ofthe Invention SEQ ID Target NO: AA Residue Contacts Most Critical AAsRelB 367 Leu-281, Ile-283, Cys-284, Glu-298, Tyr-300, Glu-298, Tyr-300,Leu- Leu-301, Leu-302, Cys-303, Ile-311, Ser-312, 302, Asp-330, Gln-334,Ala-329, Asp-330, Val-331, His-332, Gln-334, Leu-371 Leu-371 TGFβ 368Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Asp-27, Leu-28, Trp-30,Trp-32, Tyr-39, Phe-43, Pro-80, Leu-83, Leu-101, Trp-32 Ser-112 Notch1369 Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala- Phe-1520, Trp-1557,1553, Glu-1556, Trp-1557, Cys-1562, His-1602, Cys-1562, Phe-1703Arg-1684, Gln-1685, Cys-1686, Ser-1691, Cys- 1693, Phe-1694, Phe-1703Wnt8R 370 Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr- Tyr-52, Phe-57,Tyr-100, 100, Lys-101, Pro-103, Pro-105, Pro-106, Arg- Asp-145 137,Asp-145 TRAIL 371 Ala-123, His-161, Ser-162, Phe-163, Tyr-183, Phe-163,Tyr-243, Glu- Tyr-185, Tyr-243, His-270, Glu-271, Phe-274 271, Phe-278Phe-278, Leu-279, Val-280 IL6R 372 Leu-108, Glu-140, Pro-162, Phe-229,Tyr-230, Glu-140, Phe-229, Tyr- Phe-279 230, Phe-279 IL10R 373 Leu-41,Arg-42, Tyr-43, Ile-45, Glu-46, Ser-47, Tyr-43, Ile-45, Glu-46, Trp-48,Arg-76, Arg-78 Trp-48 EGFR 374 Leu-10, Thr-40, Trp-41, Asp-48, Phe-51,Leu-63, Trp-41, Asp-48, Phe-51, His-66, Asp-68, Leu-88, Tyr-101 Asp-68,Tyr-101, CDK6 375 Val-142, Arg-144, Asp-145, Ser-171, Val-180, Asp-145,Val-180, Tyr- Val-181, Leu-183, Arg-186, Val-190, Gln-193, 196 Tyr-196,Val-200 HMT 376 Tyr-16, Glu-48, Tyr-50, Leu-51, Phe-52, Asn-69 Tyr-16,Glu-48, Tyr-50, Leu-51, Phe-52, Asn-69 CD47 377 Tyr-37, Thr-49, Phe-50,Asp-51, Ala-53, Glu-97, Tyr-37, Glu-97, Glu-100, Val-98, Glu-100,Leu-101, Thr-102, Glu-104, Leu-101, Glu-104, Glu- Glu-106, Gly-107 106SIRP-α 378 Tyr-50, Gln-52, Pro-58, Ser-66, Thr-67, Ser-77 Tyr-50,Gln-52, Ser-66, Thr-67 CD206 379 Phe-708, Thr-709, Trp-710, Pro-714.Glu-719, Phe-708, Trp-710, Trp- Asn-720, Trp-721, Ala-722, Glu-725,Tyr-729, 721, Glu-725, Tyr-729, Glu-733, Asn-747, Asp-748, Ser-1691,Cys-1693, Glu-733 Phe-1694, Phe-1703 TGM2 380 Cys-277, His-335, Asp-358Cys-277, His-335, Asp- 358

Given the large number of immunologically important signaling proteinsthat are targeted by the peptides of the invention, the data suggeststhat the peptides act in a pleiotropic manner, making many differentinteractions that sum together to create a broad anti-inflammatoryresponse. This may make possible a reduction in disease conditionswithout the toxicity observed in the use of more highly-targetedchemotherapeutic agents.

Example 5 Binding of Peptides to Histone Modifying Enzymes andRibonuclease Reductase

A number of the peptides of the invention were observed to sharestructural characteristics of the N-terminal regions of histones.Accordingly, representative peptides were evaluated in silico for theirability to bind to histone modification enzymes. In this manner, it wasdiscovered that the peptides of the invention have high binding affinityfor histone methyl transferase (HMT)(NCBI Acc. No. NP_048968.1; SEQ IDNO: 376), binding close to the active site of the enzyme. Predictedbinding energies of select peptides of the invention for HMT, calculatedusing the ClusPro™ algorithm, are shown in Table 14. Again, thepredicted binding energies correlate well with the predicted energiesfor binding RelB.

TABLE 14 Binding Affinities of Select Peptides to HMT, MKK7, and RNR SEQID RP# Sequence NO: RelB HMT 185 FFKKFFKKFK 123 −920.6 −846.4 186KFKKFFKKFF 124 −919.6 −795.7 183 FFRKFAKRFK 122 −933.2 −839.4 182KFRKAFKRFF 121 −944.8 −826.6 118 FFFRFFFNFN 44 −1,139.9 −1,000.2 394NFNFFFRFFF 33 −1,286.6 −998.4 389 FRFKFA 257 −1,009.8 −836.8 390 FRFKFKF256 −1,083.3 −906.6 391 FRFKFKFR 254 −1,190.8 −949.2 392 RFQFKFRF 255−1,170.3 −962.2 387 AAKKAAKKAK 173 −301.6 −334.5 *All binding affinitiesare in kcal/mol.

A model of Histone Methyl Transferase (HMT) bound by RP-182 is shown inFIG. 13. The orange amino acids are the active site of the histonemethyl transferase enzyme. Inhibition of methyl transferase activity byRP-182 is expected since RP-182 binds to at least one residue of theactive site, in a manner that appears to obstruct access to the activesite. A non-exhaustive list of amino acid residues in HMT that are boundby the peptides of the invention is shown in Table 13, above.

Peptides of the invention are also observed to display strong predictedaffinities to MAP kinase kinase 7 (MKK7; SEQ ID NO: 166), a member ofthe mitogen-activated protein kinase kinase family involved in signaltransduction mediating cell responses to proinflammatory cytokines, andtherefore likely involved in peptides' anti-inflammatory activity. Thepredicted affinity of e.g. RP-182 for MKK7 is −738.2 kcals/mol.

In addition, peptides of the invention were observed to displaysubstantial predicted affinities to ribonuclease reductase (RNR; SEQ IDNO: 168) also known as ribonucleoside diphosphate reductase. This is anenzyme that catalyzes the formation of deoxyribonucleotides fromribonucleotides. Deoxyribonucleotides in turn are used in the synthesisof DNA. The reaction catalyzed by RNR is strictly conserved in allliving organisms. Furthermore, RNR plays a critical role in regulatingthe total rate of DNA synthesis, so that DNA to cell mass is maintainedat a constant ratio during cell division and DNA repair. A somewhatunusual feature of the RNR enzyme is that it catalyzes a reaction thatproceeds via a free radical mechanism of action. The substrates for RNRare ADP, GDP, CDP and UDP. dTDP (deoxythymidine diphosphate) issynthesized by another enzyme (thymidylate kinase) from dTMP(deoxythymidine monophosphate). The predicted affinity of e.g. RP-182for RNR is −814.0 kcals/mol.

Example 6 Binding of Peptides to Targets Associated with MacrophageActivation

Peptides of the invention are also predicted to interact with severalproteins relevant to macrophage activity and apoptosis, propertiesassociated with inflammation and with tumor genesis and metastasis.Targets identified to date include CD47, SIRP-α, CD206, TGM2, LEGUMAIN,DC-SIGN, CSF1, CSF1R, and IL34.

CD47 (or “Cluster of Differentiation 47”), also known as integrinassociated protein (IAP), is a transmembrane protein that belongs to theimmunoglobulin superfamily. CD47 protein partners with membrane-boundcellular adhesion receptors known as integrins and also binds theligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha(SIRP-α). CD47 is involved in a range of cellular processes, includingapoptosis, proliferation, adhesion, and migration. Furthermore, it playsa key role in immune and angiogenic responses. CD47 is expressed in manytypes of human cells and has been found to be overexpressed in manydifferent types of tumors. The overexpression of CD47 has receivedconsiderable attention as a possible protective agent for human cancers.By binding to SIRP-α on the surface of macrophages. CD47 is believed tosend a “don't eat me” signal that disables the macrophages fromattacking the cancer cell.

CD206 and TGM2 have likewise been identified as potentially importantregulators of macrophage activity. CD206 is a C-type lectin, primarilypresent on the surface of macrophages and dendritic cells. It is thefirst member of a family of endocytic receptors that includes Endo 180(CD280), M-type PLA2R, and DEC-205 (CD205). The receptor recognizesterminal mannose. N-acetylglucosamine, and fucose residues that make upglycans, which are attached to proteins found on the surface of somemicroorganisms. Accordingly, the CD206 receptor appears to play a rolein both the innate and adaptive immune systems. In addition,tumor-associated macrophages may use CD206 to ingest collagen, yieldingdegradation products capable of nourishing both themselves and tumorcells, and weakening collagen binding of tumor cells so as to encouragemetastasis.

TGM2 belongs to a family of enzymes that catalyze the calcium-dependenttranslational modification of proteins. The family members are foundboth intracellularly and extracellularly. TGM2 is unique in the familybecause of its multi-functionality and specialized structure, whichincludes four distinct domains: an N-terminal β-sandwich that containsfibronectin and integrin binding sites; a catalytic core that containsthe catalytic triad for acyl-transfer reactions (Cys-277, His-335, andAsp-358); and two C-terminal β-barrel domains, with the second having aphospholipase-binding sequence. TGM2 has been implicated as a regulatorof extracellular matrix functions, including cell adhesion andmigration, cellular growth and differentiation, apoptosis, tumor growth,and wound healing. Although TGM2 is ubiquitously expressed, it is mosthighly expressed in M2 macrophages. Furthermore, increased TGM2 levelsare associated with scleroderma, lung and kidney fibrosis, worseningsymptoms for diabetes, arthritis, and EAE, and poor outcomes in a numberof different cancers, all of which can be linked to M2 macrophages.

Predicted binding energies of select peptides of the invention for CD47(NCBI Acc. No. XP_005247966.1; SEQ ID NO: 377), SIRP-α (GenBank Acc. No.AAH26692.1; SEQ ID NO: 378), CD206 (NCBI Acc. No. NP_002429.1; SEQ IDNO: 379), and TGM2 (GenBank Acc. No. AAB95430.1; SEQ ID NO: 380)calculated using the ClusPro™ algorithm, are shown in Table 15. As withthe other targets discussed above, the predicted binding energiescorrelate well with the predicted energies for binding RelB.

LEGUMAIN is a protein that in humans is encoded by the LGMN gene. Thisgene encodes a cysteine protease, legumain that has a strict specificityfor hydrolysis of asparaginyl bonds. This enzyme may be involved in theprocessing of bacterial peptides and endogenous proteins for MHC classII presentation in the lysosomal/endosomal systems. Enzyme activation istriggered by acidic pH and appears to be autocatalytic. Proteinexpression occurs after monocytes differentiate into dendritic cells. Afully mature, active enzyme is produced following lipopolysaccharideexpression in mature dendritic cells. Overexpression of this gene may beassociated with the majority of solid tumor types. LEGUMAIN is alsooverexpressed in M2 macrophages, and inhibition of its activity by thedisclosed peptides is expected to downregulate M2-activated macrophages.

DC-SIGN (Dendritic Cell-Specific Intercellular adhesionmolecule-3-Grabbing Non-integrin) also known as CD209 (Cluster ofDifferentiation 209) is a protein that in humans is encoded by the CD209gene. DC-SIGN is a C-type lectin receptor present on the surface of bothmacrophages and dendritic cells. DC-SIGN on macrophages recognizes andbinds to mannose type carbohydrates, a class of pathogen associatedmolecular patterns PAMPs commonly found on viruses, bacteria and fungi.This binding interaction activates phagocytosis. On myeloid andpre-plasmacytoid dendritic cells DC-SIGN mediates dendritic cell rollinginteractions with blood endothelium and activation of CD4+ T cells, aswell as recognition of pathogen haptens. DC-SIGN is significantlyoverexpressed in M2 macrophages, and inhibition of its activity by thedisclosed peptides is expected to downregulate M2-activated macrophages.

TABLE 15 Binding Affinities of Select Peptides to CD47, SIRP-α, CD206,and TGM2 RP# Sequence SEQ ID NO: RelB SIRP-α CD47 CD206 TGM2 185FFKKFFKKFK 123 −920.6 −799.2 −639.3 −807.1 −827.2 186 KFKKFFKKFF 124−919.6 −711.8 −637.4 −881.3 −885.3 183 FFRKFAKRFK 122 −933.2 −834.2−658.1 −786.7 −860.7 182 KFRKAFKRFF 121 −944.8 −733.1 −723.1 −844.5−869.1 118 FFFRFFFNFN 44 −1,139.9 −805.2 −751.5 −1,048.7 n/a 394NFNFFFRFFF 33 −1,286.6 −854.2 −751.5 −986.6 n/a 389 FRFKFA 257 −1,009.8−934.6 −688.3 −861.9 n/a 390 FRFKFKF 256 −1,083.3 −887.2 −783.5 −978.1n/a 391 FRFKFKFR 254 −1,190.8 −932.1 −790.1 −941.3 n/a 392 RFQFKFRF 255−1,170.3 −982.5 −792.1 −981.6 n/a 387 AAKKAAKKAK 173 −301.6 −392.3−308.7 −416.6 n/a *All binding affinities are in kcal/mol.

FIG. 14 (left panel) shows a model of the ecto-domain of a CD47 dimer(top view) (SEQ ID NO: 377), with magenta- and cyan-colored surfacesrepresenting the polar and non-polar amino acids, respectively, that areinvolved in the binding of CD47 to the SIRP-α receptor. FIG. 14 (rightpanel) is a model of the ecto-domain of the CD47 dimer when bound byRP-183 (SEQ ID NO: 121). Based on this predicted interaction betweenRP-183 and CD47, peptides of the invention are expected to block theinteraction between CD47 and SIRP-α.

FIG. 15 shows a model of a SIRP-α dimer (SEQ ID NO: 378), with magenta-and cyan-colored surfaces representing the polar and non-polar aminoacids involved in its binding to CD47 (see left-most dimer). In aslightly-skewed view of the same SIRP-α dimer bound by RP-183 (SEQ IDNO: 122) (see right-most dimer), it can be seen that RP-183 bindstightly to the amino acids involved in binding to the CD47 receptor. Ittherefore appears that RP-183 (and other peptides of the invention)block the interaction between CD47 and SIRP-α by two distinctmechanisms, binding to the corresponding binding sites in both CD47 andSIRP-α. Thus, predicted activities associated with the peptides of theinvention include thwarting of an important defense mechanism for cancercells.

Peptides of the invention are also predicted to block key sites on theCD206 receptor subunit. FIG. 16 shows a model of CD206 (SEQ ID NO: 379)bound by RP-182 (SEQ ID NO: 121). The cyan-colored tyrosine residue onthe bend region of CD206 (left-most molecule) forms a planar,hydrophobic stacking interactions with the mannose ligands on thesurface of target cells. The magenta colored amino acids are acidicresidues that help chelate the required calcium ion necessary for stableinteractions with the mannose receptor. The RP-182 peptide (seen in meshon the right-most molecule) blocks activity by interacting with both ofthese key sites on the receptor subunit. Peptides of the invention aretherefore expected to reduce the viability of M2 macrophages, which hasbeen experimentally confirmed (as set forth below).

Furthermore, peptides of the invention are predicted to block the activesite of TGM2. FIG. 17 (left panel) shows a model of TGM2 (SEQ ID NO:380) with the active site residues highlighted in blue. FIG. 17 (rightpanel) shows the same model of TGM2 bound by RP-182 (SEQ ID NO: 121),which is colored magenta. As can be seen, RP-182 is predicted to bind toTGM2 in a manner that completely covers the active site, therebyobstructing substrate access and inhibiting TGM2 function.Significantly, decreased levels of TGM2 is associated with reduced NF-kBactivation, so the interaction of the polypeptides of the invention withTGM2 would appear to reinforce and/or augment their suppression of NF-kBactivity.

Non-exhaustive lists of specific amino acid residues in CD47, SIRP-α,CD206, and TGM2 that are bound by the peptides of the invention areshown in Table 13, above.

Example 7 Binding of Peptides to Checkpoint Inhibitors and RelatedTargets

It has also been observed that peptides of the present invention displaysubstantial affinity to checkpoint inhibitor proteins and their ligands.Such proteins, including cytotoxic T-lymphocyte antigen 4 (CTLA-4),PD-1, and other inhibitory coreceptors, expressed on the surface ofeffector immune cells, when activated appear to exhaust the activity ofthe immune cells, serving as immune checkpoints in order to preventuncontrolled immune reactions. Tumor cells often express ligands to thecheckpoint inhibitors, e.g. PD-L1 and PD-L2, attenuating the capacity ofthe immune system to attack the tumor.

In particular, programmed cell death protein 1, also known as PD-1 andCD279 (cluster of differentiation 279), is a protein that in humans isencoded by the PDCD1 gene. PD-1 is a cell surface receptor that belongsto the immunoglobulin superfamily and is expressed on T cells and pro-Bcells. PD-1 binds two ligands, PD-L1 and PD-L2. PD-1, functioning as animmune checkpoint plays an important role in downregulating the immunesystem by preventing the activation of T-cells, which in turn reducesautoimmunity and promotes self-tolerance. The inhibitory effect of PD-1is accomplished through a dual mechanism of promoting apoptosis(programmed cell death) in antigen specific T-cells in lymph nodes whilesimultaneously reducing apoptosis in regulatory T cells (suppressor Tcells).

Programmed death-ligand 1 (PD-L1) also known as cluster ofdifferentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that inhumans is encoded by the CD274 gene. Programmed death-ligand 1 (PD-L1)is a 40 kDa type I transmembrane protein that has been speculated toplay a major role in suppressing the immune system during particularevents such as pregnancy, tissue allografts, autoimmune disease andother disease states such as hepatitis. Normally the immune systemreacts to foreign antigens where there is some accumulation in the lymphnodes or spleen that triggers a proliferation of antigen-specific CD8+ Tcell. The formation of PD-1 receptor/PD-L1 or B7.1 receptor/PD-L1 ligandcomplex transmits an inhibitory signal which reduces the proliferationof these CD8+ T cells at the lymph nodes and supplementary to that PD-1is also able to control the accumulation of foreign antigen specific Tcells in the lymph nodes through apoptosis which is further mediated bya lower regulation of the gene Bcl-2.

As illustrations of the binding of peptides of the present inventionwith checkpoint inhibitors and their ligands, the predicted affinity ofRP-182 to PD-1 is −742.9, and that of RP-621 is −1,008.8. The affinityof RP-182 to PD-L1 is −677.4, and that of RP-621 to PD-L1 is −1,010.6.As with inflammatory targets, there is a striking correlation amongpredicted affinities to several other checkpoint inhibitors and theirligands, as well as other proteins known to play a role in modulatingthe immune apparatus. These include: TIM-1 (believed to play a role inT-helper cell development: predicted affinity to RP-182, −850.1); CTLA-4(checkpoint inhibitor: predicted affinity to RP-182, −663.2); ADORA2a(modulates activity of neutrophils and mast cells: predicted affinity toRP-182, −938.7); OX40 (secondary co-stimulatory immune checkpoint:predicted affinity to RP-182, −759.9); IDO (immune checkpoint: predictedaffinity to RP-182, −934.0); LAG-3 (immune checkpoint receptor:predicted affinity to RP-182, −873.1); CD73 (enzyme limiting T cellactivity through adenosine receptor signaling: predicted affinity ofCD73-I to RP-182, −808.7; predicted affinity of CD73-II to RP-182,−949.1); Arginase-1 (blocks activity of cytotoxic T lymphocytes:predicted affinity to RP-182, −984.2); Colony Stimulating Factor 1(blockade shown to upregulate checkpoint molecules, as well asreprogramming macrophage responses; predicted affinity of CSF1 toRP-182, −854.7; predicted affinity of CSF1D to RP-182, −847.1; predictedaffinity of CSF1R to RP-182, −774.1); and IL34 (also activates CSF1R;predicted affinity to RP-182, −828.5).

Example 8 Binding of Peptides to MKK7

Dual specificity mitogen-activated protein kinase kinase 7, also knownas MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encodedby the MAP2K7 gene. This protein is a member of the mitogen-activatedprotein kinase kinase family. The MKK7 protein exists as six differentisoforms with three possible N-termini (α, β, and γ isoforms) and twopossible C-termini (1 and 2 isoforms). MKK7 is involved in signaltransduction mediating the cell responses to proinflammatory cytokines,and environmental stresses. This kinase specifically activatesMAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated andactivated by MAP kinase kinase kinases including MAP3K1/MEKK1,MAP3K2/MEKK2, MAP3K3/MEKK5, and MAP4K2/GCK.

Example 9 Binding of Peptides to Serum Albumin

It is well-known that the most abundant protein in the circulation isserum albumin. It is also known that solid tumors will take up serumalbumin into their cells (through the process of pinocytosis) and use itas an energy source. Therefore, peptides of the invention were evaluatedin silico for their ability to bind to human serum albumin (HSA)(NCBIAcc. No. NP_000468.1; SEQ ID NO: 381). It was discovered that peptidesof the invention have the capacity to bind to HSA with high affinity.Predicted binding energies of select peptides of the invention forbinding to HSA are shown in Table 16, below.

TABLE 16 Binding Affinities of Select Peptides to Human Serum Albumin(HSA) SEQ ID RP# Sequence NO: RelB HSA 185 FFKKFFKKFK 123 −920.6 −880.2186 KFKKFFKKFF 124 −919.6 −850.5 183 FFRKFAKRFK 122 −933.2 −860.1 182KFRKAFKRFF 121 −944.8 −789.0 118 FFFRFFFNFN 44 −1,139.9 −1,064.7 394NFNFFFRFFF 33 −1,286.6 −1,016.5 389 FRFKFA 257 −1,009.8 −904.8 390FRFKFKF 256 −1,083.3 −1,046.0 391 FRFKFKFR 254 −1,190.8 −1,021.9 392RFQFKFRF 255 −1,170.3 −1,037.4 387 AAKKAAKKAK 173 −301.6 −410.7 *Allbinding affinities are in kcal/mol.

FIG. 18 is a model of HSA (shown in green) bound by RP-183 (blue). Thecomputational modeling has identified a number of possible peptidebinding sites on HSA. Therefore, it is believed that a single HSAmolecule is able to bind to multiple peptides of the invention. Thebinding interaction between peptides of the invention and HSA suggestthat HSA could be used as an in vivo carrier of the peptides. In thismanner, HSA could protect the peptides from degradation in the blood andcarry the peptides to sites of action, such as sites of inflammationand/or cancer cells, thereby increasing the efficacy of the peptides.

Example 10 In Vitro Modulation of NF-kB Activity

NF-kB activity was monitored using the a 3T3-L1 preadipocyte cell linestably transformed with a Nfkb-RE/GFP construct, as described in Shen etal. (2013), “Adipocyte reporter assays: Application for identificationof anti-inflammatory and antioxidant properties of mangosteenxanthones,” Mol. Nutr. Food Res. 00:1-9, the entire contents of whichare incorporated herein by reference. NF-kB expressing adipocytereporter cells were plated in DMEM in wells of a 24-well plate, at aseeding density of 5×10⁴. On the second and third days post-plating,test peptides were individually added to the wells to a finalconcentration of 0.01 μM. The test peptides included RP-398 (SEQ ID NO:155), and RP-185 (SEQ ID NO: 123). On day 4 post-plating,lipopolysaccharide was added to the medium to a final concentration of20 ng/ml. Finally, on day 5 post-plating, the cells were harvested and afluorescence assay performed to detect GFP expression levels.

In this experiment, NF-kB expression was reduced approximately 58%relative to control cells that were not exposed to RP-398 or RP-185peptide.

Example 11 In Vivo Modulation of Macrophage Activity

A frequently observed phenotype associated with tumor genesis andmetastasis is the polarization of macrophage cells into the “M2”transition state, in which they are in an inflammatory state. Suchmacrophages are among those designated as “tumor-associated macrophages”(TAMs). To determine whether the peptides of the invention couldinfluence macrophage polarization, the following experiment wasperformed.

Primary bone marrow cells were collected from male C57BL/6J (The JacksonLaboratory, Bar Harbor, Me.). Mouse bone marrow macrophages weredifferentiated in vitro from the primary bone marrow cells by culturingin Dulbecco's minimal essential medium (DMEM) with 10% FBS and 30 ng/mlmurine M-CSF (colony stimulating factor) for 6 days. At day 7,macrophages were plated into 12-well plates and cultured in DMEM (10%FBS) with (i) IL-4 peptide (20 ng/mL), (ii) INF-γ (10 ng/mL), or (iii)neither IL-4 nor INF-γ for 24 hours. After 24 hours, the media wasreplaced with pure DMEM and the cells were cultured for an additional 48hours. The resulting macrophages were (i) M2-polarized, (ii)M1-polarized, or (iii) undifferentiated, respectively.

A macrophage sample containing approximately 70,000 undifferentiatedmacrophages per ml was incubated for 72 hours with 100 nM RP-182 (SEQ IDNO: 121). Following the incubation, a count of viable cells revealedthat there were 68,000 cells per ml. Similarly, incubating M1-polarizedmacrophages for 72 hours with 100 nM RP-182 resulted in a viable cellcount of 68.000 cells per ml. Thus, the RP-182 had little effect on theviability of M1 macrophages. In contrast, incubating M2-polarizedmacrophages for 72 hours with 100 nM RP-182 resulted in a viable cellcount of only 20.000 cells per ml. The results indicate that RP-182reduces the viability of M2 macrophages.

Example 12 Downregulation of Checkpoint Inhibitors and Ligands

Based on their predicted affinity to checkpoint inhibitors (e.g. PD-1)and their ligands (e.g. PD-L1 and PD-L2), the polypeptides of theinvention were also evaluated to determine whether the concentration ofthese proteins in treated tissue would be downregulated in vivo. In oneexperiment, tumors in transgenic p53/KRAS mice were allowed to grow toapproximately 100 m³ in volume, and the animals were then treated dailysubcu for one week with either vehicle only, or 10 mg/kg RP-182,following which the animals were sacrificed and the tumors resected,formalin-fixed, and stained with antibodies to PD-1 (FIG. 19), PD-L1 andPD-L2 (FIG. 20). It is clear from the figures that both the checkpointinhibitor PD-1 and each of its ligands PD-L1 and PD-L2 are significantlydownregulated in vivo in tissue treated with peptides of the presentdisclosure.

Example 13 Suppression of Tumor Growth

The polypeptides of the invention were also tested for their effect ontumor growth in a mouse model of non-metastatic breast cancer. MCF-7human non-metastatic breast cancer cells were cultured at 37° C., 5% CO2in normal growth media. Cells were harvested at 80% to 90% confluence.Immune compromised athymic nude mice (J:NU) were divided into 2 groups(9 animals per group). All mice were injected with ˜4.5×10⁶ MCF-7 cellswhich had been stained with VIVO Tracker 680 and suspended in 200 μl ofPBS/Matrigel mixture. Cells were injected subcutaneously on the dorsalsurface of treated animals using a 22 gauge needle fitted with a 500 μlsyringe.

Animals were designated vehicle and peptide treated. The peptide treatedanimals were treated with the RP-397 polypeptide (SEQ ID NO: 194).Freshly prepared RP-397 peptide was dissolved in sterile saline at aconcentration of 100 μM and was used to treat the animals in the peptidegroup. Vehicle treated animals were injected with saline buffer alone.All treatments were injected into the tumor mass two times weekly for 5weeks using a 27 gauge needle fitted with a 1 ml syringe. Animal weightsand tumor volumes were measured 3 times weekly and the fluorescencelabeling was followed by VIVO Tracker 680 and IVIS Imaging. The resultsare shown in Table 17, below.

TABLE 17 Suppression of Tumor Growth Using RP-397 Avg. Tumor Rate ofTumor Body Weight Body Weight Weight Growth Before After Vehicle 1.5 g63  25.2 30.2 RP-397 0.75 g* 20* 25.1 30.1 The rate of tumor growth wasmeasured in mm³/day. The “*” denotes a statistically significantdifference from the vehicle control.

The data shows that polypeptides of the invention can suppress tumorgrowth in vivo.

Example 14 Administering Peptides in Combination with Chemotherapy

Given the significant role of inflammation in tumor genesis andmetastasis, as well as the known association of M2 macrophage activitywith tumor development, it was anticipated that the administration ofpeptides of the invention could positively influence the outcomes ofcancer treatment.

To test this theory, cohorts of immunocompromised (“nude”) mice wereinjected with ˜5×10⁶ human triple-negative breast cancer cells(MDA-MB-231) under the upper left teat. Following this administration,one cohort received only vehicle; two of the cohorts received thechemotherapeutic agent Gemcitabine, at a q4d dose of 40 mg/kg of bodyweight. One of these cohorts also received RP-182 (SEQ ID NO: 121) at adaily dose of 5 mg/kg body weight; and a fourth cohort received onlyRP-182 at a daily dose of 5 mg/kg body weight. Beginning on day 32 ofthe study, in the Gemcitabine+RP-182 cohort, concentrations of RP-182were increased to 20 mg/kg body weight. Tumor volume was assessed atvarious time points following initial cell administration (FIG. 21).After 50 days, the mice were sacrificed.

The data demonstrates that, as compared to treatment with Gemcitabinealone, combined treatment with Gemcitabine and polypeptides of theinvention resulted in reductions in mean tumor volume. When RP-182concentration was increased to 20 mg/kg body weight, the increase intumor volume was essentially halted.

In a second experiment, xenografts of C42B prostate cancer cells wereintroduced into four cohorts of mice, and the tumors allowed to grow toapproximately 100 m³ before treatment. One cohort was treated only withvehicle; a second with Docetaxel at 2.5 mg/kg body weight administeredweekly; a third with RP-182 administered daily subcu at 10 mg/kg bodyweight; and a fourth with both Docetaxel at 2.5 mg/kg weekly and RP-182at 10 mg/kg daily. Tumor volume was assessed at various time pointsfollowing initial cell administration (FIG. 22); after 27 days, the micewere sacrificed. Similarly, the administration of RP-182 plus Docetaxelresulted in decreases in mean tumor volume compared to Docetaxel alone.

It is anticipated that the peptides of the invention will producesynergistic effects when administered with chemotherapeutic agents otherthan Gemcitabine and Docetaxel, as well as checkpoint inhibitortherapies and other immunotherapies. In particular, the peptides of theinvention may be particularly useful when used in conjunction withrecently-developed CAR-T (chimeric antigen receptor/T cell) therapies.Such therapies, while destroying tumor cells, create a very highsystemic burden of dead cell material, overstimulating the immune systemand creating a “cytokine storm” which can be fatal to the patient.

EMBODIMENTS

The following embodiments are provided to illustrate aspects of thepresent invention.

1. An anti-inflammatory composition comprising a peptide, wherein thepeptide is 3 to 24 amino acid residues in length and comprises astriapathic region consisting of alternating X_(m) and Y_(n) modules,wherein m and n are positive integers that identify different modules,wherein each X_(m) module consists of a sequence according to theformula X_(ma)-X_(mb)-X_(mc)-X_(md)-X_(me), wherein X_(ma) is selectedfrom the group consisting of a naturally occurring hydrophilic aminoacid, a non-naturally occurring hydrophilic amino acid, and ahydrophilic amino acid mimetic, and wherein X_(mb), X_(mc), X_(md) andX_(me) are each individually absent or selected from the groupconsisting of a naturally occurring hydrophilic amino acid, anon-naturally occurring hydrophilic amino acid, and a hydrophilic aminoacid mimetic, wherein each Y_(n) module consists of a sequence accordingto the formula Y_(na)-Y_(nb)-Y_(nc)-Y_(nd)-Y_(ne), wherein Y_(na) isselected from the group consisting of a naturally occurring hydrophobicamino acid, a non-naturally occurring hydrophobic amino acid, and ahydrophobic amino acid mimetic, and wherein Y_(nb), Y_(nc), Y_(nd), andY_(ne) are each individually absent or selected from the groupconsisting of a naturally occurring hydrophobic, a non-naturallyoccurring hydrophobic amino acid, and a hydrophobic amino acid mimetic,and wherein the peptide binds to the dimerization site on a NFkB ClassII protein.

2. The anti-inflammatory composition of embodiment 1, wherein each X_(m)module consists of a sequence according to the formulaX_(ma)-X_(mb)-X_(mc)-X_(md), and each Y_(n) module consists of asequence according to the formula Y_(na)-Y_(nb)-Y_(nc)-Y_(nd).

3. The anti-inflammatory composition of embodiment 1, wherein each X_(m)module consists of a sequence according to the formulaX_(ma)-X_(mb)-X_(mc), and each Y_(n) module consists of a sequenceaccording to the formula Y_(na)-Y_(nb)-Y_(nc).

4. The anti-inflammatory composition of any one of embodiments 1 to 3,wherein the peptide also binds to human serum albumin.

5. The anti-inflammatory composition of any one of embodiments 1 to 4,wherein the striapathic region of the peptide contains at least twoX_(m) modules (X₁, X₂, and X₃) and at least two Y_(n) modules (Y₁, Y₂,and Y₃).

6. The anti-inflammatory composition of any one of embodiments 1 to 5,wherein the striapathic region of the peptide contains at least sevenamino acid residues.

7. The anti-inflammatory composition of any one of embodiments 1 to 6,wherein the striapathic region of the peptide has a length of 7 to 12amino acid residues.

8. The anti-inflammatory composition of any one of embodiments 1 to 7,wherein the striapathic region of the peptide constitutes at least 25%of the length of the peptide.

9. The anti-inflammatory composition of any one of embodiments 1 to 8,wherein the striapathic region of the peptide has an amphipathicconformation under physiological conditions.

10. The anti-inflammatory composition of embodiment 9, wherein thestriapathic region of the peptide has an amphipathic 3₁₀-helicalconformation, an amphipathic α-helical conformation, or an amphipathicπ-helical conformation when bound to the NFkB Class II protein.

11. The anti-inflammatory composition of embodiment 10, wherein theamphipathic 3₁₀-helical, α-helical, or π-helical conformation includes ahydrophobic portion having a facial are of at least 100°.

12. The anti-inflammatory composition of any one of embodiments 1 to 11,wherein the striapathic region contains hydrophobic amino acid residueshaving a total volume of at least 650 cubic angstroms.

13. The anti-inflammatory composition of any one of embodiments 1 to 12,wherein the striapathic region is characterized by a ratio of the sum ofthe volume of hydrophobic amino acid residues to the sum of the volumeof hydrophilic amino acid residues, wherein the ratio is at least 0.75or higher.

14. The anti-inflammatory composition of embodiment 9, wherein thestriapathic region of the peptide comprises at least one proline residueand adopts an amphipathic conformation that includes a proline-richhelix.

15. The anti-inflammatory composition of embodiment 9, wherein thestriapathic region of the peptide adopts an amphipathic beta-strandconformation.

16. The anti-inflammatory composition of any one of embodiments 1 to 13,wherein the striapathic region includes a sequence selected from thegroup of sequences defined by Formula I:Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c) (Formula I).

17. The anti-inflammatory composition of embodiment 16, wherein themodule Y_(1a)-Y_(1b)-Y_(1c) has a sequence selected from the groupconsisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), Tyr-Tyr-Tyr (YYY),Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met (MMM), Val-Val-Val(VVV), and Ile-Ile-Ile (III).

18. The anti-inflammatory composition of embodiment 16, wherein themodule Y_(1a)-Y_(1b)-Y_(1c) has a sequence selected from the groupconsisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), and Tyr-Tyr-Tyr(YYY).

19. The anti-inflammatory composition of any one of embodiments 16 to18, wherein the module Y_(2a)-Y_(2b)-Y_(2c) has a sequence selected fromthe group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW),Tyr-Tyr-Tyr (YYY), Leu-Leu-Leu (LLL), Cys-Cys-Cys (CCC), Met-Met-Met(MMM), Val-Val-Val (VVV), and Ile-Ile-Ile (III).

20. The anti-inflammatory composition of any one of embodiments 16 to18, wherein the module Y_(2a)-Y_(2b)-Y_(2c) has a sequence selected fromthe group consisting of Phe-Phe-Phe (FFF), Trp-Trp-Trp (WWW), andTyr-Tyr-Tyr (YYY).

21. The anti-inflammatory composition of embodiment 16, wherein thestriapathic region includes a sequence selected from the groupconsisting of FFF-X_(1a)-FFF (SEQ ID NO: 1), WWW-X_(1a)-WWW (SEQ ID NO:2), and YYY-X_(1a)-YYY (SEQ ID NO: 3).

22. The anti-inflammatory composition of embodiment 16, wherein thesequence of the three modules is selected from the group consisting ofLLL-X_(1a)-LLL (SEQ ID NO: 4), CCC-X_(1a)-CCC (SEQ ID NO: 5),MMM-X_(1a)-MMM (SEQ ID NO: 6), VVV-X_(1a)-VVV (SEQ ID NO: 7), andIII-X_(1a)-III (SEQ ID NO: 8).

23. The anti-inflammatory composition of any one of embodiments 16 to22, wherein X_(1a) is selected from the group consisting of Arg (R), His(H), and Lys (K).

24. The anti-inflammatory composition of any one of embodiments 16 to22, wherein X_(1a) is selected from the group consisting of Glu (E), Gln(Q), Asn (N), and Asp (D).

25. The anti-inflammatory composition of any one of embodiments 16 to24, wherein the striapathic region includes a sequence selected from thegroup of sequences defined by Formula II or the group of sequencesdefined by Formula III:Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)(Formula II);X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2b)-Y_(2c) (FormulaIII).

26. The anti-inflammatory composition of embodiment 25, wherein X_(2a)and X_(3a) are each individually selected from the group consisting ofArg (R), His (H), Lys (K), Glu (E), Gln (Q), Asn (N), and Asp (D).

27. The anti-inflammatory composition of embodiment 25, wherein X_(2a)and X_(3a) are each individually selected from the group consisting ofGlu (E), Gln (Q), Asn (N), and Asp (D).

28. The anti-inflammatory composition of any one of embodiments 25 to27, wherein Y_(3a) is selected from the group consisting of Phe (F), Trp(W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), and ne (I).

29. The anti-inflammatory composition of any one of embodiments 25 to27, wherein Y_(3a) is selected from the group consisting of Phe (F), Trp(W), Tyr (Y), and Leu (L).

30. The anti-inflammatory composition of embodiment 25, wherein thesequence of X_(2a)-Y_(3a)-X_(3a) is selected from the group consistingof EFQ, EFE, EFN, EFD, NFQ, NFE, NFN, NFD, QFQ, QFE, QFN, QFD, DFQ, DFE,DFN, DFD, EWQ, EWE, EWN, EWD, NWQ, NWE, NWN, NWD, QWQ, QWE, QWN, QWD,DWQ, DWE, DWN, DWD, EYQ, EYE, EFN, EYD, NYQ, NYE, NYN, NYD, QYQ, QYE,QYN, QYD, DYQ, DYE, DYN, DYD, ELQ, ELE, ELN, ELD, NLQ, NLE, NLN, NLD,QLQ, QLE, QLN, QLD, DLQ, DLE, DLN, DLD, RFR, RFQ, RFE, RFN, RFD, RWR,RWQ, RWE, RWN, and RWD.

31. The anti-inflammatory composition of embodiment 25, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP394, RP108-RP123,RP125-131, RP133, RP135-RP141, RP143-RP146, RP148-RP150, RP152-RP165,RP179, RP395, RP211, RP230, RP232, RP258, RP267, RP268, RP271, andRP273.

32. The anti-inflammatory composition of embodiment 25, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP113 (SEQ ID NO: 39),RP118 (SEQ ID NO: 44), and RP394 (SEQ ID NO: 33).

33. The anti-inflammatory composition of any one of embodiments 1 to 13,wherein the striapathic region includes a sequence selected from thegroup of sequences defined by Formula VII:Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a) (Formula VII).

34. The anti-inflammatory composition of embodiment 33, wherein Y_(2a)is selected from the group consisting of Phe (F), Trp (W), and Tyr (Y).

35. The anti-inflammatory composition of embodiment 33, wherein Y_(2a)is selected from the group consisting of Leu (L), Cys (C), Met (M), Val(V), Ile (I), and Ala (A).

36. The anti-inflammatory composition of any one of embodiments 33 to35, wherein Y_(2b) is selected from the group consisting of Phe (F), Trp(W), and Tyr (Y).

37. The anti-inflammatory composition of any one of embodiments 33 to35, wherein Y_(2b) is selected from the group consisting of Leu (L), Cys(C), Met (M), Val (V), Ile (I), and Ala (A).

38. The anti-inflammatory composition of any one of embodiments 33 to37, wherein X_(1b) is selected from the group consisting of Arg (R), Lys(K), and His (H).

39. The anti-inflammatory composition of any one of embodiments 33 to37, wherein X_(1b) is selected from the group consisting of Asn (N), Gln(Q), Asp (D), and Glu (E).

40. The anti-inflammatory composition of any one of embodiments 33 to39, wherein X_(2a) is selected from the group consisting of Arg (R), Lys(K), and His (H).

41. The anti-inflammatory composition of any one of embodiments 33 to39, wherein X_(2a) is selected from the group consisting of Asn (N), Gln(Q), Asp (D), and Glu (E).

42. The anti-inflammatory composition of embodiment 33, wherein thesequence X_(1b)-Y_(2a)-Y_(2b)-X_(2a) is selected from the groupconsisting of Lys-Phe-Phe-Lys (KFFK; SEQ ID NO: 386), Lys-Trp-Trp-Lys(KWWK; SEQ ID NO: 387), Lys-Tyr-Try-Lys (KYYK; SEQ ID NO: 388),Lys-Phe-Trp-Lys (KFWK; SEQ ID NO: 389), Lys-Trp-Phe-Lys (KWFK; SEQ IDNO: 390), Lys-Phe-Tyr-Lys (KFYK; SEQ ID NO: 391), Lys-Tyr-Phe-Lys (KYFK;SEQ ID NO: 392), Lys-Trp-Tyr-Lys (KWYK; SEQ ID NO: 393), andLys-Tyr-Trp-Lys (KYWK; SEQ ID NO: 394).

43. The anti-inflammatory composition of embodiment 33, wherein thesequence X_(1b)-Y_(2a)-Y_(2b)-X_(2a) is selected from the groupconsisting of Arg-Phe-Phe-Arg (RFFR; SEQ ID NO: 395), Arg-Trp-Trp-Arg(RWWR; SEQ ID NO: 396), Arg-Tyr-Try-Arg (RYYR; SEQ ID NO: 397),Arg-Phe-Trp-Arg (RFWR; SEQ ID NO: 398), Arg-Trp-Phe-Arg (RWFR; SEQ IDNO: 399), Arg-Phe-Tyr-Arg (RFYR; SEQ ID NO: 400), Arg-Tyr-Phe-Arg (RYFR;SEQ ID NO: 401), Arg-Trp-Tyr-Arg (RWYR; SEQ ID NO: 402), andArg-Tyr-Trp-Arg (RYWR; SEQ ID NO: 403).

44. The anti-inflammatory composition of embodiment 33, wherein thesequence X_(1b)-Y_(2a)-Y_(2b)-X_(2a) is selected from the groupconsisting of His-Phe-Phe-His (HFFH; SEQ ID NO: 404), His-Trp-Trp-His(HWWH; SEQ ID NO: 405), His-Tyr-Try-His (HYYH; SEQ ID NO: 406),His-Phe-Trp-His (HFWH; SEQ ID NO: 407), His-Trp-Phe-His (HWFH; SEQ IDNO: 408), His-Phe-Tyr-His (HFYH; SEQ ID NO: 409), His-Tyr-Phe-His (HYFH;SEQ ID NO: 410). His-Trp-Tyr-His (HWYH; SEQ ID NO: 411), andHis-Tyr-Trp-His (HYWH; SEQ ID NO: 132).

45. The anti-inflammatory composition of any one of embodiments 33 to44, wherein X_(1a) is selected from the group consisting of Arg (R), Lys(K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

46. The anti-inflammatory composition of any one of embodiments 33 to44, wherein X_(1a) is selected from the group consisting of Arg (R) andGln (Q).

47. The anti-inflammatory composition of any one of embodiments 33 to46, wherein X_(2b) is selected from the group consisting of Arg (R), Lys(K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

48. The anti-inflammatory composition of any one of embodiments 33 to46, wherein X_(2b) is selected from the group consisting of Arg (R) andGln (Q).

49. The anti-inflammatory composition of any one of embodiments 33 to48, wherein Y_(1a) is selected from the group consisting of Phe (F), Trp(W), and Tyr (Y).

50. The anti-inflammatory composition of any one of embodiments 33 to48, wherein Y_(1a) is selected from the group consisting of Leu (L), Cys(C), Met (M), Val (V), Ile (I), and Ala (A).

51. The anti-inflammatory composition of any one of embodiments 33 to50, wherein Y_(3a) is selected from the group consisting of Phe (F), Trp(W), and Tyr (Y).

52. The anti-inflammatory composition of any one of embodiments 33 to50, wherein Y_(3a) is selected from the group consisting of Leu (L), Cys(C), Met (M), Val (V), Ile (I), and Ala (A).

53. The anti-inflammatory composition of embodiment 33, wherein thestriapathic region includes a sequence selected from the groupconsisting of F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F (SEQ ID NO: 9),F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-W (SEQ ID NO: 10),W-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F (SEQ ID NO: 11),F-X_(1a)-X_(1b)-FW-X_(2a)-X_(2b)-F (SEQ ID NO: 12),F-X_(1a)-X_(1b)-WF-X_(2a)-X_(2b)-F (SEQ ID NO: 13),F-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-F (SEQ ID NO: 14),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-F (SEQ ID NO: 15),F-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 16),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 17),F-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-Y (SEQ ID NO: 18),Y-X_(1a)-X_(1b)-FF-X_(2a)-X_(2b)-F (SEQ ID NO: 19),F-X_(1a)-X_(1b)-FY-X_(2a)-X_(2b)-F (SEQ ID NO: 20),F-X_(1a)-X_(1b)-YF-X_(2a)-X_(2b)-F (SEQ ID NO: 21),F-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-F (SEQ ID NO: 22),Y-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-F (SEQ ID NO: 23),F-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 24), andY-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 25),Y-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-W (SEQ ID NO: 26),W-X_(1a)-X_(1b)-YY-X_(2a)-X_(2b)-Y (SEQ ID NO: 27),Y-X_(1a)-X_(1b)-YW-X_(2a)-X_(2b)-Y (SEQ ID NO: 28),Y-X_(1a)-X_(1b)-WY-X_(2a)-X_(2b)-Y (SEQ ID NO: 29),Y-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-Y (SEQ ID NO: 30),W-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-X-Y (SEQ ID NO: 31), andY-X_(1a)-X_(1b)-WW-X_(2a)-X_(2b)-W (SEQ ID NO: 32).

54. The anti-inflammatory composition of embodiment 53, wherein X_(1a),X_(1b), X_(2a), and X_(2b) are each independently selected from thegroup consisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp(D), and Glu (E).

55. The anti-inflammatory composition of embodiment 53 or 54, whereinX_(1b) and X_(2a) are each independently selected from the groupconsisting of Arg (R), Lys (K), and His (H).

56. The anti-inflammatory composition of any one of embodiments 33 to55, wherein the striapathic region includes a first additional aminoacid residue directly bound to Y_(1a) of Formula VII, wherein the firstadditional amino acid residue is a hydrophobic amino acid residue.

57. The anti-inflammatory composition of embodiment 56, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

58. The anti-inflammatory composition of any one of embodiments 33 to55, wherein the striapathic region includes a first additional aminoacid residue directly bound to Y_(3a) of Formula VII, wherein the firstadditional amino acid residue is a hydrophobic amino acid residue.

59. The anti-inflammatory composition of embodiment 58, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

60. The anti-inflammatory composition of any one of embodiments 33 to55, wherein the striapathic region includes a first additional aminoacid residue directly bound to Y_(1a)of Formula VII, wherein the firstadditional amino acid residue is a hydrophilic amino acid residue.

61. The anti-inflammatory composition of embodiment 60, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

62. The anti-inflammatory composition of any one of embodiments 33 to55, wherein the striapathic region includes a first additional aminoacid residue directly bound to Y_(3a) of Formula VII, wherein the firstadditional amino acid residue is a hydrophilic amino acid residue.

63. The anti-inflammatory composition of embodiment 62, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

64. The anti-inflammatory composition of 56, 57, 60, or 61, wherein thestriapathic region includes a second additional amino acid residuedirectly bound to Y_(3a) of Formula VII, wherein the second additionalamino acid residue is a hydrophobic amino acid residue.

65. The anti-inflammatory composition of embodiment 64, wherein thesecond additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

66. The anti-inflammatory composition of 58, 59, 62, or 63, wherein thestriapathic region includes a second additional amino acid residuedirectly bound to Y_(1a) of Formula VII, wherein the second additionalamino acid residue is a hydrophilic amino acid residue.

67. The anti-inflammatory composition of embodiment 66, wherein thesecond additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

68. The anti-inflammatory composition of embodiment 33, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP124, RP132, RP134,RP142, RP147, RP151, RP166-RP172, RP175, RP177, RP182, RP183, RP185,RP186, RP 424, RP190, RP194, RP198, RP199-RP202, RP204, RP206, RP207,RP209, RP210, RP212-RP216, RP218, RP219, RP425, RP225, RP227,RP233-RP239. RP398, RP241-RP247, RP250-RP256, and RP426.

69. The anti-inflammatory composition of embodiment 33, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP124 (SEQ ID NO: 106),RP166 (SEQ ID NO: 112), RP182 (SEQ ID NO: 121), and RP183 (SEQ ID NO:122).

70. The anti-inflammatory composition of any one of embodiments 1 to 15,wherein the striapathic region includes a sequence selected from thegroup of sequences defined by any one of Formulas I-XLVIII andL:Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)Y_(2a)-Y_(2b)-Y_(2c) (Formula I);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)(Formula II);X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)(Formula III); X_(1a)-X_(1b)-X_(1c)-Y_(2a)-X_(2a)-X_(2b)-X_(2c) (FormulaIV); Y_(1a)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-X_(2b)-X_(2c)-Y_(3a)-X_(3a)(Formula V); X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b) (Formula VI);Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a) (Formula VII);Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)-X_(3a)(Formula VIII);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)(Formula IX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-X_(3a)(Formula X);X_(1a)-Y_(1a)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)(Formula XI);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(1b)-X_(3a)-X_(3b)-Y_(3a)(Formula XII);Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)(Formula XIII);X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-Y_(2c)(Formula XIV);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)(Formula XV);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)(Formula XVI); Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b) (Formula XVII);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a) (Formula XVIII);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)(Formula XIX);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)(Formula XX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b) (FormulaXXI);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-X_(3a)-Y_(3a)-Y_(3b)(Formula XXII);Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)-X_(3a)(Formula XXIII); X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)(Formula XXIV);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)-X_(3b)(Formula XXV);X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)-Y_(3c)(Formula XXVI); X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c) (FormulaXXVII); X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d) (FormulaXXVIII);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)-X_(2a)(Formula XXIX);X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)(Formula XXX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-X_(2b)(Formula XXXI);X_(1a)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)-X_(3c)-Y_(3a)-Y_(3b)-Y_(3c)(Formula XXXII); Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c) (FormulaXXXIII); Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(1a)-X_(1b)-X_(1c)-X_(1d)(Formula XXXIV);X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(2a)-X_(2b)-X_(2c)-X_(2d)-Y_(2a)(Formula XXXV);Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)(Formula XXXVI);X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-Y_(2b)(Formula XXXVII);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1a)-X_(1c)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)(Formula XXXVIII); Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1c)-Y_(2a)(Formula XXXIX);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)(Formula XL);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)(Formula XLI);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)(Formula XLII);Y_(1a)-Y_(1b)-Y_(1c)-Y_(1e)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)(Formula XLIII); X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)(Formula XLIV);X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)-X_(2d)(Formula XLV);X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)(Formula XLVI);X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)(Formula XLVII);X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)(Formula XLVIII); andY_(1a)-Y_(1b)-X_(1a)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)-Y_(4a)(Formula L).

71. The anti-inflammatory composition of embodiment 70, wherein Y_(1a),Y_(1b), Y_(1c), Y_(2a), Y_(2b), Y_(2c), Y_(3a), Y_(3b), and Y_(3c) areeach individually selected from the group consisting of Phe (F), Trp(W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A).

72. The anti-inflammatory composition of embodiment 70, wherein Y_(1a),Y_(1b), Y_(1c), Y_(2a), Y_(2b), Y_(2c), Y_(3a), Y_(3b), and Y_(3c) areeach individually selected from the group consisting of Phe (F), Trp(W), and Tyr (Y).

73. The anti-inflammatory composition of any one of embodiments 70 to72, wherein X_(1a), X_(1b), X_(1c), X_(2a), X_(2b), X_(2c), X_(3a), andX_(3b) are each individually selected from the group consisting of Arg(R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).

74. The anti-inflammatory composition of any one of embodiments 70 to73, wherein X_(1a), X_(1b), X_(1c), X_(2a), X_(2b), X_(2c), X_(3a), andX_(3b) are each individually selected from the group consisting of Arg(R), Lys (K), His (H), and Gln (Q).

75. The anti-inflammatory composition of any one of embodiments 70 to74, wherein the striapathic region includes a first additional aminoacid residue directly bound to the N-terminal end of any one of FormulasI-XLVIII and L, wherein the first additional amino acid residue is ahydrophobic amino acid residue.

76. The anti-inflammatory composition of embodiment 70, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

77. The anti-inflammatory composition of any one of embodiments 70 to74, wherein the striapathic region includes a first additional aminoacid residue directly bound to the C-terminal end of any one of FormulasI-XLVIII and L, wherein the first additional amino acid residue is ahydrophobic amino acid residue.

78. The anti-inflammatory composition of embodiment 77, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

79. The anti-inflammatory composition of any one of embodiments 70 to74, wherein the striapathic region includes a first additional aminoacid residue directly bound to the N-terminal end of any one of FormulasI-XLVIII and L, wherein the first additional amino acid residue is ahydrophilic amino acid residue.

80. The anti-inflammatory composition of embodiment 79, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

81. The anti-inflammatory composition of any one of embodiments 70 to74, wherein the striapathic region includes a first additional aminoacid residue directly bound to the C-terminal end of any one of FormulasI-XLVIII and L, wherein the first additional amino acid residue is ahydrophilic amino acid residue.

82. The anti-inflammatory composition of embodiment 81, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

83. The anti-inflammatory composition of any one of embodiments 75, 76,79, or 80, wherein the striapathic region includes a second additionalamino acid residue directly bound to the C-terminal end of any one ofFormulas I-XLVIII and L, wherein the second additional amino acidresidue is a hydrophobic amino acid residue.

84. The anti-inflammatory composition of embodiment 83, wherein thesecond additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

85. The anti-inflammatory composition of any one of embodiments 77, 78,81, or 82, wherein the striapathic region includes a second additionalamino acid residue directly bound to the N-terminal end of any one ofFormulas I-XLVIII and L, wherein the second additional amino acidresidue is a hydrophilic amino acid residue.

86. The anti-inflammatory composition of embodiment 81, wherein thesecond additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

87. The anti-inflammatory composition of embodiment 70, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP396, RP405, RP174,RP176, RP178, RP180-181, RP184, RP408, RP187, RP416, RP188, RP189,RP388, RP417, RP191-RP193, RP404, RP196, RP397, RP197, RP402, RP203,RP409, RP205, RP208, RP217, RP220-RP224, RP226, RP229, RP231, RP240,RP248, RP249, RP415, RP257, RP259-RP266, RP269, RP272, RP406, RP422,RP407, RP400, RP419, RP401, RP423, RP411, RP418, RP428, RP420, RP421,RP429, RP413, RP430, RP270.

88. The anti-inflammatory composition of any one of embodiments 1 to 9or 15, wherein the striapathic region includes a sequence selected fromthe group of sequences defined by Formula XLIX:

Y_(1a)-X_(1a)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)  (Formula XLIX).

89. The anti-inflammatory composition of embodiment 88, wherein Y_(1a),Y_(2a), and Y_(3a) are each independently selected from the groupconsisting of Phe (F), Trp (W), Tyr (Y), Leu (L), Ile (I), Cys (C), andMet (M).

90. The anti-inflammatory composition of embodiment 88, wherein Y_(1a),Y_(2a), and Y_(3a) are each independently selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

91. The anti-inflammatory composition of any one of embodiments 88 to90, wherein X_(1a), X_(2a), and X_(3a) are each independently selectedfrom the group consisting of Arg (R), Lys (K), His (H), Gln (Q), Glu(E), Asn (N), and Asp (D).

92. The anti-inflammatory composition of any one of embodiments 88 to90, wherein X_(1a), X_(2a), and X_(3a) are each independently selectedfrom the group consisting of Arg (R), Lys (K), and His (H).

93. The anti-inflammatory composition of any one of embodiments 88 to92, wherein the striapathic region includes a first additional aminoacid residue directly bound to Y_(1a) of Formula XLIX, wherein the firstadditional amino acid residue is a hydrophilic amino acid residue.

94. The anti-inflammatory composition of embodiment 93, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), His (H), Asn (N), Gln (Q), Asp (D), andGlu (E).

95. The anti-inflammatory composition of embodiment 93, wherein thefirst additional amino acid residue is selected from the groupconsisting of Arg (R), Lys (K), and His (H).

96. The anti-inflammatory composition of any one of embodiments 88 to92, wherein the striapathic region includes a first additional aminoacid residue directly bound to X_(3a) of Formula XLIX, wherein the firstadditional amino acid residue is a hydrophobic amino acid residue.

97. The anti-inflammatory composition of embodiment 96, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), andMet (M).

98. The anti-inflammatory composition of embodiment 96, wherein thefirst additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and (Tyr).

99. The anti-inflammatory composition of any one of embodiments 93 to95, wherein the striapathic region includes a second additional aminoacid residue directly bound to X_(3a) of Formula XLIX, wherein thesecond additional amino acid residue is a hydrophobic amino acidresidue.

100. The anti-inflammatory composition of embodiment 99, wherein thesecond additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), (Tyr), Leu (L), Ile (I), Cys (C), andMet (M).

101. The anti-inflammatory composition of embodiment 99, wherein thesecond additional amino acid residue is selected from the groupconsisting of Phe (F), Trp (W), and Tyr (Y).

102. An anti-inflammatory composition comprising a peptide, wherein thepeptide is 3 to 24 amino acids residues in length and comprises astriapathic region having at least 70% identity with the sequenceNFNFFFRFFF (RP394, SEQ ID NO: 33), wherein the peptide binds to thedimerization site on a NFkB Class II protein.

103. The anti-inflammatory composition of embodiment 102, wherein thepeptide also binds to human serum albumin.

104. The anti-inflammatory composition of embodiment 102 or 103, whereinthe differences between the striapathic region of the peptide and thesequence NFNFFFRFFF (SEQ ID NO: 33) are limited to conservative orhighly conservative amino acid substitutions.

105. The anti-inflammatory composition of embodiment 102 or 103, whereinthe striapathic region of the peptide differs from the sequenceNFNFFFRFFF (SEQ ID NO: 33) by substitution of one or more of thephenylalanine (F) residues with an amino acid residue selected from thegroup consisting of Trp (W), Tyr (Y), His (H), and Leu (L).

106. The anti-inflammatory composition of embodiment 102 or 103, whereinthe striapathic region of the peptide differs from the sequenceNFNFFFRFFF (SEQ ID NO: 33) by the deletion of one, two, or three aminoacids.

107. The anti-inflammatory composition of embodiment 106, wherein thedeleted amino acids are located at the N-terminal end, the C-terminalend, or both ends of the sequence NFNFFFRFFF (SEQ ID NO: 33).

108. An anti-inflammatory composition comprising a peptide, wherein thepeptide is 3 to 24 amino acids residues in length and comprises astriapathic region having at least 70% identity with the sequenceFFFRFFFNFN (RP118, SEQ ID NO: 44), wherein the peptide binds to thedimerization site on a NFkB Class II protein.

109. The anti-inflammatory composition of embodiment 108, wherein thepeptide also binds to human serum albumin.

110. The anti-inflammatory composition of embodiment 108 or 109, whereinthe differences between the striapathic region of the peptide and thesequence FFFRFFFNFN (SEQ ID NO: 44) are limited to conservative orhighly conservative amino acid substitutions.

111. The anti-inflammatory composition of embodiment 108 or 109, whereinthe striapathic region of the peptide differs from the sequenceFFFRFFFNFN (SEQ ID NO: 44) by substitution of one or more of thephenylalanine (F) residues with an amino acid residue selected from thegroup consisting of Trp (W), Tyr (Y), His (H), and Leu (L).

112. The anti-inflammatory composition of embodiment 108 or 109, whereinthe striapathic region of the peptide differs from the sequenceFFFRFFFNFN (SEQ ID NO: 44) by the deletion of one, two, or three aminoacids.

113. The anti-inflammatory composition of embodiment 112, wherein thedeleted amino acids are located at the N-terminal end, the C-terminalend, or both ends of the sequence FFFRFFFNFN (SEQ ID NO: 44).

114. An anti-inflammatory composition comprising a peptide, wherein thepeptide is 3 to 24 amino acids residues in length and comprises astriapathic region having at least 70% identity with the sequenceFFRKFAKRFK (RP183, SEQ ID NO: 122), wherein the peptide binds to thedimerization site on a NFkB Class II protein.

115. The anti-inflammatory composition of embodiment 114, wherein thepeptide also binds to human serum albumin.

116. The anti-inflammatory composition of embodiment 114 or 115, whereinthe differences between the striapathic region of the peptide and thesequence FFRKFAKRFK (SEQ ID NO: 122) are limited to conservative orhighly conservative amino acid substitutions.

117. The anti-inflammatory composition of embodiment 114 or 115, whereinthe striapathic region of the peptide differs from the sequenceFFRKFAKRFK (SEQ ID NO: 122) by substitution of one or more of thephenylalanine (F) residues with an amino acid residue selected from thegroup consisting of Trp (W), Tyr (Y), and Leu (L).

118. The anti-inflammatory composition of embodiment 114 or 115, whereinthe striapathic region of the peptide differs from the sequenceFFRKFAKRFK (SEQ ID NO: 122) by the deletion of one, two, or three aminoacids.

119. The anti-inflammatory composition of embodiment 118, wherein thedeleted amino acids are located at the N-terminal end, the C-terminalend, or both ends of the sequence FFRKFAKRFK (SEQ ID NO: 122).

120. An anti-inflammatory composition comprising a peptide, wherein thepeptide is 3 to 24 amino acids residues in length and comprises astriapathic region having at least 70% identity with the sequenceKFRKAFKRFF (RP182, SEQ ID NO: 121), wherein the peptide binds to thedimerization site on a NFkB Class II protein.

121. The anti-inflammatory composition of embodiment 120, wherein thepeptide also binds to human serum albumin.

122. The anti-inflammatory composition of embodiment 120 or 121, whereinthe differences between the striapathic region of the peptide and thesequence KFRKAFKRFF (SEQ ID NO: 121) are limited to conservative orhighly conservative amino acid substitutions.

123. The anti-inflammatory composition of embodiment 120 or 121, whereinthe striapathic region of the peptide differs from the sequenceKFRKAFKRFF (SEQ ID NO: 121) by substitution of one or more of thephenylalanine (F) residues with an amino acid residue selected from thegroup consisting of Trp (W), Tyr (Y), and Leu (L).

124. The anti-inflammatory composition of embodiment 120 or 121, whereinthe striapathic region of the peptide differs from the sequenceKFRKAFKRFF (SEQ ID NO: 121) by the deletion of one, two, or three aminoacids.

125. The anti-inflammatory composition of embodiment 124, wherein thedeleted amino acids are located at the N-terminal end, the C-terminalend, or both ends of the sequence KFRKAFKRFF (SEQ ID NO: 121).

126. The anti-inflammatory composition of any one of embodiments 1 to125, wherein the peptide binds to the dimerization site on Rel B (SEQ IDNO: 367) with a binding energy of at least −650 kcal/mol.

127. The anti-inflammatory composition of any one of embodiments 1 to126, wherein the peptide binds to the dimerization site on Rel B (SEQ IDNO: 367) and directly contacts at least one amino acid residue of Rel Bselected from the group consisting of Glu 298, Tyr-300, Leu-301,Leu-302, Asp-330, His-332, and Leu-371.

128. The anti-inflammatory composition of embodiment 127, wherein thepeptide, when bound to the dimerization site on Rel B, forms an ionicbond with Asp-330, forms an ionic bond with His-332, and/or makes ahydrophobic contact with Leu-371.

129. The anti-inflammatory composition of any one of embodiments 1 to128, wherein the peptide binds to at least one signaling moleculeselected from the group consisting of TGFβ (SEQ ID NO: 368), Notch1 (SEQID NO: 369), Wnt8R (SEQ ID NO: 370), TRAIL (SEQ ID NO: 371), IL6R (SEQID NO: 372), IL10R (SEQ ID NO: 373), EGFR (SEQ ID NO: 374), CDK6 (SEQ IDNO: 375), Histone Methyl Transferase (HMT) (SEQ ID NO: 376), CD47 (SEQID NO: 377), SIRP-α (SEQ ID NO: 378), CD206 (SEQ ID NO: 379), TGM2 (SEQID NO: 380); LEGUMAIN (SEQ ID NO: 137), CD209 (SEQ ID NO: 140), FAS (SEQID NO: 152), PD-1 (SEQ ID NO: 159), MKK7 (SEQ ID NO: 166), and RNR (SEQID NO: 168).

130. The anti-inflammatory composition of embodiment 129, wherein thepeptide binds to TGFβ (SEQ ID NO: 368) with a binding energy of at least−650 kcal/mol.

131. The anti-inflammatory composition of embodiment 129 or 130, whereinthe peptide binds to TGFβ (SEQ ID NO: 368) and directly contacts atleast one amino acid residue of TGFβ selected from the group consistingof Leu-20, Ile-22, Phe-24, Asp-27, Leu-28, Trp-30, Trp-32, Tyr-39,Phe-43, Pro-80, Leu-83, Leu-101, and Ser-112.

132. The anti-inflammatory composition of any one of embodiments 129 to131, wherein the peptide binds to Notch1 (SEQ ID NO: 369) with a bindingenergy of at least −650 kcal/mol.

133. The anti-inflammatory composition of any one of embodiments 120 to123, wherein the peptide binds to Notch (SEQ ID NO: 369) and directlycontacts at least one amino acid residue of Notch selected from thegroup consisting of Phe-1520, Gln-1523, Arg-1524, Glu-1526, Ala-1553,Glu-1556, Trp-1557, Cys-1562, His-1602, Arg-1684, Gln-1685, Cys-1686,Ser-1691, Cys-1693, Phe-1694, and Phe-1703.

134. The anti-inflammatory composition of any one of embodiments 129 to133, wherein the peptide binds to Wnt8R (SEQ ID NO: 370) with a bindingenergy of at least −600 kcal/mol.

135. The anti-inflammatory composition of any one of embodiments 129 to134, wherein the peptide binds to Wnt8R (SEQ ID NO: 370) and directlycontacts at least one amino acid residue of Wnt8R selected from thegroup consisting of Tyr-52, Gln-56, Phe-57, Asn-58, Met-91, Tyr-100,Lys-101, Pro-103, Pro-105, Pro-106, Arg-137, and Asp-145.

136. The anti-inflammatory composition of any one of embodiments 129 to135, wherein the peptide binds to TRAIL (SEQ ID NO: 371) with a bindingenergy of at least −650 kcal/mol.

137. The anti-inflammatory composition of any one of embodiments 120 to127, wherein the peptide binds to TRAIL (SEQ ID NO: 371) and directlycontacts at least one amino acid residue of TRAIL selected from thegroup consisting of Arg-130, Arg-158, Ser-159, Gly-160, His-161,Phe-163. Tyr-189, Arg-189, Gln-193, Glu-195, Glu-236, Tyr-237, Leu-239,Asp-267, Asp-269, His-270, and Glu-271.

138. The anti-inflammatory composition of any one of embodiments 129 to137, wherein the peptide binds to IL6R (SEQ ID NO: 372) with a bindingenergy of at least −600 kcal/mol.

139. The anti-inflammatory composition of any one of embodiments 129 to138, wherein the peptide binds to IL6R (SEQ ID NO: 372) and directlycontacts at least one amino acid residue of IL6R selected from the groupconsisting of Glu-163, Gly-164, Phe-168, Gln-190, Phe-229, Tyr-230,Phe-279, and Gln-281.

140. The anti-inflammatory composition of any one of embodiments 129 to139, wherein the peptide binds to IL10R (SEQ ID NO: 373) with a bindingenergy of at least −600 kcal/mol.

141. The anti-inflammatory composition of any one of embodiments 129 to140, wherein the peptide binds to IL10R (SEQ ID NO: 373) and directlycontacts at least one amino acid residue of IL10R selected from thegroup consisting of Tyr-43, Ile-45, Glu-46, Asp-61, Asn-73, Arg-76,Asn-94, Arg-96, Phe-143, Ala-189, Ser-190, and Ser-191.

142. The anti-inflammatory composition of any one of embodiments 129 to141, wherein the peptide binds to EGFR (SEQ ID NO: 374) with a bindingenergy of at least −650 kcal/mol.

143. The anti-inflammatory composition of any one of embodiments 129 to142, wherein the peptide binds to EGFR (SEQ ID NO: 374) and directlycontacts at least one amino acid residue of EGFR selected from the groupconsisting of Leu-10, Thr-40, Trp-41, Leu-63, His-66, Asp-68, Leu-88,Tyr-101, Asp-48, and Phe-51.

144. The anti-inflammatory composition of any one of embodiments 129 to143, wherein the peptide binds to CDK6 (SEQ ID NO: 375) with a bindingenergy of at least −600 kcal/mol.

145. The anti-inflammatory composition of any one of embodiments 129 to144, wherein the peptide binds to CDK6 (SEQ ID NO: 375) and directlycontacts at least one amino acid residue of CDK6 selected from the groupconsisting of Val-142, Arg-144, Asp-145, Ser-171, Val-180, Val-181,Leu-183, Arg-186, Val-190, Gln-193, Tyr-196, and Val-200.

146. The anti-inflammatory composition of any one of embodiments 129 to145, wherein the peptide binds to histone methyl transferase (HMT) (SEQID NO: 376) with a binding energy of at least −600 kcal/mol.

147. The anti-inflammatory composition of any one of embodiments 129 to146, wherein the peptide binds to HMT (SEQ ID NO: 376) and directlycontacts at least one amino acid residue of HMT selected from the groupconsisting of Asn-69, His-70, Ser-71, Lys-72, Asp-73, Pro-74, andAsn-75.

148. The anti-inflammatory composition of any one of embodiments 129 to147, wherein the peptide binds to the SIRP-α binding site on CD47 (SEQID NO: 377) with a binding energy of at least −550 kcal/mol.

149. The anti-inflammatory composition of any one of embodiments 129 to148, wherein the peptide binds to CD47 (SEQ ID NO: 377) and directlycontacts at least one amino acid residue of CD47 selected from the groupconsisting of Glu-29, Ala-30, Glu-35, Val-36, Tyr-37, Lys-39, Thr-49,Asp-51, Glu-97, Thr-99, Leu-101, Thr-102, Arp-103, Glu-104, and Glu-106.

150. The anti-inflammatory composition of any one of embodiments 129 to149, wherein the peptide binds to the CD47 binding site on SIRP-α (SEQID NO: 378) with a binding energy of at least −600 kcal/mol.

151. The anti-inflammatory composition of any one of embodiments 129 to150, wherein the peptide binds to SIRP-α (SEQ ID NO: 378) and directlycontacts at least one amino acid residue of SIRP-α selected from thegroup consisting of Leu-30, Gln-37, Gln-52, Lys-53, Ser-66, Thr-67,Arg-69, Met-72, Phe-74, Lys-96, and Asp-100.

152. The anti-inflammatory composition of any one of embodiments 129 to151, wherein the peptide binds to CD206 (SEQ ID NO: 379) with a bindingenergy of at least −650 kcal/mol.

153. The anti-inflammatory composition of any one of embodiments 129 to152, wherein the peptide binds to CD206 (SEQ ID NO: 379) and directlycontacts at least one amino acid residue of CD206 selected from thegroup consisting of Glu-725, Tyr-729, Glu-733, Asn-747, and Asp-748.

154. The anti-inflammatory composition of any one of embodiments 129 to153, wherein the peptide binds to TGM2 (SEQ ID NO: 380) with a bindingenergy of at least −650 kcal/mol.

155. The anti-inflammatory composition of any one of embodiments 129 to154, wherein the peptide binds to TGM2 (SEQ ID NO: 380) and directlycontacts at least one amino acid residue of TGM2 selected from the groupconsisting of Cys-277, His-335, and Asp-358.

156. The anti-inflammatory composition of any one of embodiments 129 to155, wherein the peptide binds to LEGUMAIN (SEQ ID NO: 137) with abinding energy of at least −600 kcal/mol.

157. The anti-inflammatory composition of any one of embodiments 129 to156, wherein the peptide binds to LEGUMAIN (SEQ ID NO: 137) and directlycontacts at least one amino acid residue of LEGUMAIN selected from thegroup consisting of Asn-44, Arg-46, His-159, Glu-189, Cys-191, Ser-217,Ser-218 and Asp-233.

158. The anti-inflammatory composition of any one of embodiments 129 to157, wherein the peptide binds to CD209 (SEQ ID NO: 140) with a bindingenergy of at least −600 kcal/mol.

159. The anti-inflammatory composition of any one of embodiments 129 to158, wherein the peptide binds to CD209 (SEQ ID NO: 140) and directlycontacts at least one amino acid residue of CD209 selected from thegroup consisting of Phe-269, Glu-280, Glu-303, Asn-305, Asn-306,Glu-310, Asp-311, Ser-316, Gly-317, Asn-321 and Lys-324.

160. The anti-inflammatory composition of any one of embodiments 129 to159, wherein the peptide binds to FAS (SEQ ID NO: 152) with a bindingenergy of at least −600 kcal/mol.

161. The anti-inflammatory composition of any one of embodiments 129 to160, wherein the peptide binds to FAS (SEQ ID NO: 152) and directlycontacts at least one amino acid residue of FAS selected from the groupconsisting of Lys-251, Lys-296, Lys-299, Leu-303, Leu-306, Ala-307,Glu-308, Lys-309, Gln-311, Ile-314, Leu-315, Asp-317, Ile-318 andThr-319.

162. The anti-inflammatory composition of any one of embodiments 129 to161, wherein the peptide binds to PD-1 (SEQ ID NO: 159) with a bindingenergy of at least −600 kcal/mol.

163. The anti-inflammatory composition of any one of embodiments 129 to162, wherein the peptide binds to PD-1 (SEQ ID NO: 159) and directlycontacts at least one amino acid residue of PD-1 selected from the groupconsisting of Val-64, Asn-66. Tyr-68, Met-70, Thr-76, Lys-78, Thr-120.Leu-122, Ala-125, and Ser-127.

164. The anti-inflammatory composition of any one of embodiments 129 to163, wherein the peptide binds to MKK7 (SEQ ID NO: 166) with a bindingenergy of at least −600 kcal/mol.

165. The anti-inflammatory composition of any one of embodiments 129 to164, wherein the peptide binds to MKK7 (SEQ ID NO: 166) and directlycontacts at least one amino acid residue of MKK7 selected from the groupconsisting of Met-142, Val-150, Lys-152, Lys-165, Met-212, Met-215,Thr-217, Lys-221, Leu-266, Cys-276 and Asp-277.

166. The anti-inflammatory composition of any one of embodiments 129 to165, wherein the peptide binds to RNR (SEQ ID NO: 168) with a bindingenergy of at least −600 kcal/mol.

167. The anti-inflammatory composition of any one of embodiments 129 to166, wherein the peptide binds to RNR (SEQ ID NO: 168) and directlycontacts at least one amino acid residue of RNR selected from the groupconsisting of Asn-426, Leu-427, Cys-428, Glu-430, Met-606, Pro-608 andAla-610.

168. The anti-inflammatory composition of any one of embodiments 1 to167, wherein the peptide binds to human serum albumin (HSA) (SEQ ID NO:381) with a binding energy of at least −650 kcal/mol.

169. The anti-inflammatory composition of any one of embodiments 1 to168, wherein the peptide comprises a striapathic region that is composedexclusively of D-form amino acid residues.

170. The anti-inflammatory composition of any one of embodiments 1 to169, wherein the peptide is in solution at a concentration of about 0.1mg/ml to about 100 mg/ml.

171. The anti-inflammatory composition of any one of embodiments 1 to170, wherein the composition contains about 1 mg to about 500 mg of thepeptide.

172. The anti-inflammatory composition of embodiment 158 or 171, whereinthe composition is substantially free of protein other than the peptide.

173. An anti-inflammatory composition comprising a first peptide asdefined in any one of embodiments 1 to 171 in combination with a secondpeptide as defined in any one of embodiments 1 to 171, wherein the firstand second peptides can have the same sequence or different sequences.

174. The anti-inflammatory composition of embodiment 173, wherein thefirst and second peptides are linked together by a peptide bond, apeptide linker, or a non-peptide linker.

175. The anti-inflammatory composition of embodiment 173, wherein thefirst and second peptides are linked together by a peptide linker,wherein the peptide linker has a sequence selected from the groupconsisting of Gly-Gly-Gly (GGG), Gly-Gly-Gly-Arg (GGGR; SEQ ID NO: 412),Gly-Pro-Gly (GPG), and Gly-Pro-Gly-Arg (GPGR; SEQ ID NO: 413).

176. The anti-inflammatory composition of embodiment 174 or 175, whereinthe linked first and second peptides bind to the dimerization site onRel B (SEQ ID NO: 367) with a binding energy of at least −700 kcal/mol.

177. The anti-inflammatory composition of any one of embodiments 1 to171 and embodiments 173 to 176, further comprising serum albumin.

178. The anti-inflammatory composition of embodiment 177, wherein thecomposition is substantially free of blood proteins other than serumalbumin.

179. A pharmaceutical composition comprising the anti-inflammatorycomposition of any one of embodiments 1 to 178, and a pharmaceuticallyacceptable carrier.

180. The pharmaceutical composition of embodiment 179, wherein thecomposition comprises a chemotherapeutic agent.

181. A method of treating a condition associated with chronicinflammation, the method comprising administering a compositionaccording to any one of embodiments 1 to 180 to a subject suffering fromthe condition.

182. The method of embodiment 181, wherein the condition is selectedfrom the group consisting of irritable bowel disease, ulcerativecolitis, colitis, Crohn's disease, idiopathic pulmonary fibrosis,asthma, keratitis, arthritis, osteoarthritis, rheumatoid arthritis,auto-immune diseases, a feline or human immunodeficiency virus (FIV orHIV) infection, and cancer.

183. The method of embodiment 181 or 182, wherein the subject is amammal.

184. The method of any one of embodiments 181 to 183, wherein thesubject is a human.

185. The method of any one of embodiments 181 to 184, wherein theanti-inflammatory composition is administered in a dosage that includesbetween about 1 mg and about 500 mg of peptide.

186. The method of any one of embodiments 181 to 185, wherein theanti-inflammatory composition is administered intravenously,intraperitoneally, parenteral, orthotopically, subcutaneously,topically, nasally, by means of an implantable depot, usingnanoparticle-based delivery systems, microneedle patch, microspheres,beads, osmotic or mechanical pumps, and/or other mechanical means.

187. The method of any one of embodiments 181 to 186, wherein theanti-inflammatory composition is administered in conjunction withanother drug known to be effective in treating the condition.

188. The method of embodiment 187, wherein the anti-inflammatorycomposition is administered prior to, at the same time as, or after theadministration of the other drug.

189. A method of treating fibrosis in a subject, the method comprisingadministering a composition according to any one of embodiments 1 to 180to the subject.

190. The method of embodiment 189, wherein the fibrosis is selected fromthe group consisting of pulmonary fibrosis, dermal fibrosis, hepaticfibrosis, renal fibrosis, and fibrosis caused by ionizing radiation.

191. The method of embodiment 189 or 190, wherein the subject is amammal.

192. The method of any one of embodiments 189 to 191, wherein thesubject is a human.

193. The method of any one of embodiments 189 to 192, wherein theanti-inflammatory composition is administered in a dosage that includesbetween about 1 mg and about 500 mg of peptide.

194. The method of any one of embodiments 189 to 193, wherein theanti-inflammatory composition is administered intravenously,intraperitoneally, parenteral, orthotopically, subcutaneously,topically, nasally, by means of an implantable depot, usingnanoparticle-based delivery systems, microneedle patch, microspheres,beads, osmotic or mechanical pumps, and/or other mechanical means.

195. The method of any one of embodiments 189 to 194, wherein theanti-inflammatory composition is administered in conjunction withanother drug known to be effective in treating fibrosis.

196. The method of embodiment 195, wherein the anti-inflammatorycomposition is administered prior to, at the same time as, or after theadministration of the other drug.

197. A method of reducing pro-inflammatory cytokine levels in a subjectsuffering from a chronic inflammatory condition, the method comprisingadministering a composition according to any one of embodiments 1 to 180to the subject.

198. The method of embodiment 197, wherein the chronic inflammatorycondition is selected from the group consisting of irritable boweldisease, ulcerative colitis, colitis, Crohn's disease, idiopathicpulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis,rheumatoid arthritis, auto-immune diseases, a feline or humanimmunodeficiency virus (FIV or HIV) infection, and cancer.

199. The method of embodiment 197 or 198, wherein the method reduces thelevel of at least one cytokine selected from group consisting of NF-kB,TNFα, IL1, IL6, IL12, MMP-1, MMP-9, MCP-1, IL8, IL7, and IL23.

200. The method of embodiment 199, wherein the level of the at least onecytokine is reduced by at least 10%.

201. The method of any one of embodiments 197 to 200, wherein thesubject is a mammal.

202. The method of any one of embodiments 197 to 201, wherein thesubject is a human.

203. The method of any one of embodiments 197 to 202, wherein theanti-inflammatory composition is administered in a dosage that includesbetween about 1 mg and about 500 mg of peptide.

204. The method of any one of embodiments 197 to 203, wherein theanti-inflammatory composition is administered intravenously,intraperitoneally, parenteral, orthotopically, subcutaneously,topically, nasally, by means of an implantable depot, usingnanoparticle-based delivery systems, microneedle patch, microspheres,beads, osmotic or mechanical pumps, and/or other mechanical means.

205. The method of any one of embodiments 197 to 204, wherein theanti-inflammatory composition is administered in conjunction withanother drug known to be effective in treating the chronic inflammatorycondition that the subject is suffering from.

206. The method of embodiment 205, wherein the anti-inflammatorycomposition is administered prior to, at the same time as, or after theadministration of the other drug.

207. A method of treating cancer in a subject, the method comprisingadministering an anti-inflammatory composition according to any one ofembodiments 1 to 180 to the subject.

208. The method of embodiment 207, wherein the cancer is selected fromthe group consisting of colon cancer, and breast cancer.

209. The method of embodiment 207 or 208, wherein the anti-inflammatorycomposition is administered in conjunction with a chemotherapeutic agentor cell therapy.

210. The method of embodiment 209, wherein the chemotherapeutic agent orcell therapy is selected from the group consisting of steroids,anthracyclines, thyroid hormone replacement drugs, thymidylate-targeteddrugs, checkpoint inhibitor drugs, Chimeric Antigen Receptor/T celltherapies, and other cell therapies.

211. The method of embodiment 209, wherein the chemotherapeutic agent isselected from the group consisting of Gemcitabine, Docetaxel, Bleomycin,Erlotinib. Gefitinib, Lapatinib. Imatinib, Dasatinib, Nilotinib,Bosutinib, Crizotinib, Ceritinib, Trametinib, Bevacizumab. Sunitinib.Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab,Ipilimumab. Rapamycin, Temsirolimus, Everolimus, Methotrexate,Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin,5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, andPemetrexed.

212. The method of any one of embodiments 209 to 211, wherein theanti-inflammatory composition is administered prior to, at the same timeas, or after the administration of the chemotherapeutic agent or celltherapy.

213. The method of embodiment 207 or 208, wherein the anti-inflammatorycomposition is administered in conjunction with radiation therapy.

214. The method of embodiment 213, wherein the anti-inflammatorycomposition is administered prior to, or after the administration of theradiation therapy.

215. The method of any one of embodiments 207 to 214, wherein thesubject is a mammal.

216. The method of any one of embodiments 207 to 215, wherein thesubject is a human.

217. The method of any one of embodiments 207 to 216, wherein theanti-inflammatory composition is administered in a dosage that includesbetween about 1 mg and about 500 mg of peptide.

218. The method of any one of embodiments 207 to 217, wherein theanti-inflammatory composition is administered intravenously,intraperitoncally, parenteral, orthotopically, subcutaneously, nasally,by means of an implantable depot, using nanoparticle-based deliverysystems, microneedle patch, microspheres, beads, osmotic or mechanicalpumps, and/or other mechanical means.

What is claimed:
 1. An anti-inflammatory composition comprising apeptide, wherein the peptide is 3 to 24 amino acid residues in lengthand comprises a striapathic region consisting of alternating hydrophilicand hydrophobic modules, wherein each hydrophilic module consists offrom 1 to 5 hydrophilic amino acid residues; wherein each hydrophobicmodule consists of from 1 to 5 hydrophobic amino acid residues; andwherein the peptide binds to the dimerization site on a NFkB Class IIprotein.
 2. The anti-inflammatory composition of claim 1, wherein thealternating hydrophilic and hydrophobic modules are defined as X_(m) andY_(n) modules, respectively, wherein m and n are positive integers thatidentify different modules, wherein each X_(m) module consists of asequence according to the formula X_(ma)-X_(mb)-X_(mc)-X_(md)-X_(me),wherein X_(ma) is selected from the group consisting of a naturallyoccurring hydrophilic amino acid, a non-naturally occurring hydrophilicamino acid, and a hydrophilic amino acid mimetic, and wherein X_(mb),X_(mc), X_(md) and X_(me) are each individually absent or selected fromthe group consisting of a naturally occurring hydrophilic amino acid, anon-naturally occurring hydrophilic amino acid, and a hydrophilic aminoacid mimetic, wherein each Y_(n) module consists of a sequence accordingto the formula Y_(na)-Y_(nb)-Y_(nc)-Y_(nd)-Y_(ne), wherein Y_(na) isselected from the group consisting of a naturally occurring hydrophobicamino acid, a non-naturally occurring hydrophobic amino acid, and ahydrophobic amino acid mimetic, and wherein Y_(nb), Y_(nc), Y_(nd), andY_(ne) are each individually absent or selected from the groupconsisting of a naturally occurring hydrophobic, a non-naturallyoccurring hydrophobic amino acid, and a hydrophobic amino acid mimetic.3. The anti-inflammatory composition of claim 1 or 2, wherein thepeptide also binds to human serum albumin.
 4. The anti-inflammatorycomposition of any one of claims 1 to 3, wherein the striapathic regionof the peptide contains at least two X_(m) modules (X₁ and X₂) and atleast two Y_(n) modules (Y₁ and Y₂).
 5. The anti-inflammatorycomposition of any one of claims 1 to 4, wherein the striapathic regionof the peptide has a length of 7 to 12 amino acid residues.
 6. Theanti-inflammatory composition of any one of claims 1 to 5, wherein thestriapathic region of the peptide: (i) has an amphipathic conformationunder physiological conditions; (ii) has an amphipathic 3₁₀-helicalconformation, an amphipathic α-helical conformation, or an amphipathicπ-helical conformation when bound to the NFkB Class 11 protein; (iii)contains hydrophobic amino acid residues having a total volume of atleast 650 cubic angstroms; (iv) is characterized by a ratio of the sumof the volume of hydrophobic amino acid residues to the sum of thevolume of hydrophilic amino acid residues, wherein the ratio is at least0.75 or higher, (v) comprises at least one proline residue and adopts anamphipathic conformation that includes a proline-rich helix; or (vi)adopts an amphipathic beta-strand conformation.
 7. The anti-inflammatorycomposition of claim 6, wherein the amphipathic 3₁₀-helical, α-helical,or π-helical conformation includes a hydrophobic portion having a facialarc of at least 100°.
 8. The anti-inflammatory composition of any one ofclaims 1 to 7, wherein the striapathic region comprises a sequencedefined by a Formula selected from the group consisting of:Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (Formula VII);X_(1a)-Y_(1a)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)  (FormulaXI);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-X_(3a)  (FormulaX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)  (FormulaIX);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (Formula I);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-Y_(3a)-X_(3a)  (FormulaII);X_(2a)-Y_(3a)-X_(3a)-Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaIII);X_(1a)-X_(1b)X_(1c)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)  (Formula IV);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-X_(3a)  (FormulaV);X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)  (Formula VI);Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaVIII);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)  (FormulaXII);Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)  (FormulaXIII);X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaXIV);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-X_(2c)  (FormulaXV);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (FormulaXVI);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)  (Formula XVII);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)  (FormulaXVIII);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaXIX);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)  (FormulaXX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)  (FormulaXXI);X_(1a)-Y_(1a)-Y_(1b)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-X_(3a)-Y_(3a)-Y_(3b)  (FormulaXXII);Y_(1a)-Y_(1b)-X_(1a)-Y_(2a)-X_(2a)-X_(2b)-X_(2c)-Y_(3a)-Y_(3b)-X_(3a)  (FormulaXXIII);X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)  (Formula XXIV);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)-X_(3b)  (FormulaXXV);X_(1a)-X_(1b)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(1b)-Y_(3a)-Y_(3b)-Y_(3c)  (FormulaXXVI);X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)  (Formula XXVII);X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)  (FormulaXXVIII);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)-X_(2a)  (FormulaXXIX);X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)  (FormulaXXX);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-Y_(2a)-Y_(2b)-Y_(2c)-X_(2a)-X_(2b)  (FormulaXXXI);X_(1a)-Y_(1a)-X_(2a)-Y_(2a)-X_(3a)-X_(3b)-X_(3c)-Y_(3a)-Y_(3b)-Y_(3c)  (FormulaXXXII);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)  (Formula XXXIII);Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(1a)-X_(1b)-X_(1c)-X_(1d)  (FormulaXXXIV);X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-X_(2a)-X_(2b)-X_(2c)-X_(2d)-Y_(2a)  (FormulaXXXV);Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1c)  (FormulaXXXVI);X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-X_(2a)-X_(2b)-X_(2c)-Y_(2a)-Y_(2b)  (FormulaXXXVII);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1a)-X_(1c)-Y_(2a)-X_(2a)-Y_(3a)-X_(3a)  (FormulaXXXVIII);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)  (Formula XXXIX);Y_(1a)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)-Y_(2d)  (FormulaXL);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)-Y_(2c)  (FormulaXLI);Y_(1a)-Y_(1b)-Y_(1c)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)-Y_(2b)  (FormulaXLII);Y_(1a)-Y_(1b)-Y_(1c)-Y_(1e)-X_(1a)-X_(1b)-X_(1c)-X_(1d)-X_(1e)-Y_(2a)  (FormulaXLIII);X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)  (Formula XLIV);X_(1a)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)-X_(2d)  (FormulaXLV);X_(1a)-X_(1b)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)-X_(2c)  (FormulaXLVI);X_(1a)-X_(1b)-X_(1c)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)-X_(2b)  (FormulaXLVII);X_(1a)-X_(1b)-X_(1c)-X_(1d)-Y_(1a)-Y_(1b)-Y_(1c)-Y_(1d)-Y_(1e)-X_(2a)  (FormulaXLVIII); andY_(1a)-Y_(1b)-X_(1a)-Y_(2a)-Y_(2b)-X_(2a)-Y_(3a)-Y_(3b)-X_(3a)-Y_(4a)  (FormulaL).
 9. The anti-inflammatory composition of claim 8, wherein Y_(1a),Y_(1b), Y_(1c), Y_(2a), Y_(2b), Y_(2c), Y_(3a), Y_(3b), and Y_(3c) areeach individually selected from the group consisting of Phe (F), Trp(W), Tyr (Y), Leu (L), Cys (C), Met (M), Val (V), Ile (I), and Ala (A)and X_(1a), X_(1b), X_(1c), X_(2a), X_(2b), X_(2c), X_(3a), and X_(3b)are each individually selected from the group consisting of Arg (R), Lys(K), His (H), Asn (N), Gln (Q), Asp (D), and Glu (E).
 10. Theanti-inflammatory composition of any one of claims 1 to 9, wherein thestriapathic region comprises a sequence defined by Formula VII:Y_(1a)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)  (Formula VII).11. The anti-inflammatory composition of claim 10, wherein thestriapathic region comprises a sequence defined by a Formula selectedfrom the group consisting of:X_(1a)-Y_(1a)-X_(2a)-X_(2b)-Y_(2a)-Y_(2b)-X_(3a)-X_(3b)-Y_(3a)-Y_(3b)  (FormulaXI);Y_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2a)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-X_(3a)  (FormulaX); orY_(1a)-Y_(1b)-X_(1a)-X_(1b)-Y_(2b)-Y_(2b)-X_(2a)-X_(2b)-Y_(3a)-Y_(3b)  (FormulaIX).
 12. The anti-inflammatory composition of claim 11, wherein thestriapathic region comprises, consists essentially of, or consists of asequence selected from the group consisting of RP182 (SEQ ID NO: 121),RP398 (SEQ ID NO: 155), RP183, RP185, RP186 (SEQ ID NOs:122 t0 124,respectively), RP233 (SEQ ID NO: 148), RP261 (SEQ ID NO: 217), RP124,RP132, RP134, RP142, RP147, RP151, RP166, RP167, RP168, RP169, RP170,RP171, RP172, RP175, RP177 (SEQ ID NOs: 106 to 120, respectively),RP424, RP190, RP194, RP198, RP199, RP200, RP201, RP202, RP204, RP206,RP207, RP209, RP210, RP212, RP213, RP214, RP215, RP216, RP218, RP219,RP425, RP225, RP227 (SEQ ID NOs: 125 to 147, respectively), RP234,RP235, RP236, RP237, RP238, RP239, RP241, RP242, RP243, RP244, RP245,RP246, RP247, RP250, RP251, RP252, RP253, RP254, RP255, RP256, RP426(SEQ ID NOs: 149-170, respectively).
 13. The anti-inflammatorycomposition of claim 12, wherein the peptide comprises a striapathicregion having at least 70% identity with the sequence KFRKAFKRFF (RP182,SEQ ID NO: 121).
 14. The anti-inflammatory composition of claim 13,wherein: (i) the differences between the striapathic region of thepeptide and the sequence KFRKAFKRFF (SEQ ID NO: 121) are limited toconservative or highly conservative amino acid substitutions; (ii) thestriapathic region of the peptide differs from the sequence KFRKAFKRFF(SEQ ID NO: 121) by substitution of one or more of the phenylalanine (F)residues with an amino acid residue selected from the group consistingof Trp (W), Tyr (Y), and Leu (L); (iii) the striapathic region of thepeptide differs from the sequence KFRKAFKRFF (SEQ ID NO: 121) by thedeletion of one, two, or three amino acids.
 15. The anti-inflammatorycomposition of any one of claims 1 to 14, wherein the peptide binds tothe dimerization site on Rel B (SEQ ID NO: 367) and wherein: (i) thepeptide binds with a binding energy of at least −650 kcal/mol; (ii) thepeptide directly contacts at least one amino acid residue of Rel Bselected from the group consisting of Glu 298, Tyr-300, Leu-301,Leu-302, Asp-330, His-332, and Leu-371; or (iii) the peptide, when boundto the dimerization site on Rel B, forms an ionic bond with Asp-330,forms an ionic bond with His-332, and/or makes a hydrophobic contactwith Leu-371.
 16. The anti-inflammatory composition of any one of claims1 to 15, wherein the peptide binds to CD206 (SEQ ID NO: 379) andwherein: (i) the peptide binds to the mannose-binding site on CD206and/or interferes with or blocks the binding of SIRP-mannose to CD206;(ii) the peptide binds with a binding energy of at least −650 kcal/mol;or (iii) the peptide directly contacts at least one amino acid residueof CD206 selected from the group consisting of Phe-708, Thr-709,Trp-710, Pro-714, Glu-719, Asn-720, Trp-721, Ala-722, Glu-725, Tyr-729,Glu-733, Asn-747, Asp-748, Ser-1691, Cys-1693, Phe-1694, and Phe-1703.17. The anti-inflammatory composition of any one of claims 1 to 15,wherein the peptide binds to at least one signaling molecule selectedfrom the group consisting of TGFβ (SEQ ID NO: 368), Notch1 (SEQ ID NO:369), Wnt8R (SEQ ID NO: 370), TRAIL (SEQ ID NO: 371), IL6R (SEQ ID NO:372), IL10R (SEQ ID NO: 373), EGFR (SEQ ID NO: 374), CDK6 (SEQ ID NO:375), Histone Methyl Transferase (HMT) (SEQ ID NO: 376), CD47 (SEQ IDNO: 377), SIRP-α (SEQ ID NO: 378), CD206 (SEQ ID NO: 379), TGM2 (SEQ IDNO: 380); LEGUMAIN (SEQ ID NO: 413), CD209 (SEQ ID NO: 414), FAS (SEQ IDNO: 415), PD-1 (SEQ ID NO: 416), MKK7 (SEQ ID NO: 417), and RNR (SEQ IDNO: 418).
 18. The anti-inflammatory composition of any one of claims 1to 17, wherein the composition further comprises a second peptide asdefined in any one of claims 1 to 17, wherein the first and secondpeptides can have the same sequence or different sequences.
 19. Theanti-inflammatory composition of claim 18, wherein the first and secondpeptides are linked together by a peptide bond, a peptide linker, or anon-peptide linker.
 20. The anti-inflammatory composition of any one ofclaims 1 to 19, wherein the composition is substantially free of proteinother than (i) the peptide or (ii) the peptide and the second peptide.21. A pharmaceutical composition comprising the anti-inflammatorycomposition of any one of claims 1 to 20 and a pharmaceuticallyacceptable carrier.
 22. The pharmaceutical composition of claim 21,wherein the composition further comprises a chemotherapeutic agent orcell therapy.
 23. The pharmaceutical composition of claim 22, whereinthe chemotherapeutic agent or cell therapy is selected from the groupconsisting of steroids, anthracyclines, thyroid hormone replacementdrugs, thymidylate-targeted drugs, checkpoint inhibitor drugs, ChimericAntigen Receptor/T cell therapies, and other cell therapies.
 24. Thepharmaceutical composition of claim 23, wherein the chemotherapeuticagent is selected from the group consisting of Gemcitabine, Docetaxel,Bleomycin, Erlotinib, Gefitinib, Lapatinib, Imatinib, Dasatinib,Nilotinib, Bosutinib, Crizotinib, Ceritinib, Trametinib, Bevacizumab,Sunitinib, Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab,Ipilimumab, Rapamycin, Temsirolimus, Everolimus, Methotrexate,Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin,5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, andPemetrexed.
 25. A method of treating a condition associated with chronicinflammation, the method comprising administering a pharmaceuticalcomposition according to any one of claims 21 to 24 to a subjectsuffering from the condition.
 26. The method of claim 25, wherein thecondition is selected from the group consisting of: irritable boweldisease, ulcerative colitis, colitis, Crohn's disease, idiopathicpulmonary fibrosis, asthma, keratitis, arthritis, osteoarthritis,rheumatoid arthritis, auto-immune diseases, a feline or humanimmunodeficiency virus (FIV or HIV) infection, cancer, pulmonaryfibrosis, dermal fibrosis, hepatic fibrosis, renal fibrosis, andfibrosis caused by ionized radiation.
 27. The method of claim 23 or 24,wherein the subject is a mammal.
 28. The method of claim 27, wherein thesubject is a human.
 29. The method of any one of claims 25 to 28,wherein the method reduces the level of at least one pro-inflammatorycytokine selected from group consisting of TNFα, IL1, IL6, IL12, MMP-1,MMP-9, MCP-1, IL8, IL17, and IL23.
 30. The method of claim 29, whereinthe level of the at least one cytokine is reduced by at least 10%. 31.The method of any one of claims 25 to 30, wherein the anti-inflammatorycomposition is administered in conjunction with another drug known to beeffective in treating the condition.
 32. The method of claim 31, whereinthe drug is a chemotherapeutic agent or cell therapy.
 33. The method ofclaim 32, wherein the chemotherapeutic agent or cell therapy is selectedfrom the group consisting of steroids, anthracyclines, thyroid hormonereplacement drugs, thymidylate-targeted drugs, checkpoint inhibitordrugs, Chemeric Antigen Receptor/T cell therapies, and other celltherapies.
 34. The method of claim 33, wherein the chemotherapeuticagent is selected from the group consisting of Gemcitabine, Docetaxel,Bleomycin, Erlotinib, Gefitinib, Lapatinib, Imatinib, Dasatinib,Nilotinib, Bosutinib, Crizotinib, Ceritinib, Trametinib, Bevacizumab,Sunitinib, Sorafenib, Trastuzumab, Ado-trastuzumab emtansine, Rituximab,Ipilimumab, Rapamycin, Temsirolimus, Everolimus, Methotrexate,Doxorubicin, Abraxane, Folfirinox, Cisplatin, Carboplatin,5-fluorouracil, Teysumo, Paclitaxel, Prednisone, Levothyroxine, andPemetrexed.